1-phenyl-benzimidazole compounds and their use as GABA-A receptor modulators

ABSTRACT

Chemical compounds of the formulaas well as pharmaceutical compositions containing them and methods for their use in the treatment of disorders and diseases responsive to modulation of the GABAA receptor complex of the central nervous system, such disorders and diseases including anxiety, sleep disorders, anesthesia, memory disorders, and epilepsy and other convulsive disorders.

This application is a 37 C.F.R. §1.53(b) divisional of application Ser.No. 09/269,643 filed on Mar. 31, 1999, now U.S. Pat. No. 6,218,547.application Ser. No. 09/269,643 now U.S. Pat. No. 6,218,547 is thenational phase under 35 U.S.C. §371 of PCT International Application No.PCT/DK97/00462, which has an international filing date of Oct. 21, 1997,which designates the United States of America.

TECHNICAL FIELD

The present invention relates to novel benzimidazole compounds,pharmaceutical compositions containing these compounds, methods oftreating therewith, and to method of preparing such benzimidazolecompounds. The novel compounds of the invention are useful in thetreatment of central nervous system diseases and disorders, which areresponsive to modulation of the GABA_(A) receptor complex, such as forexample anxiety, sleep disorders, anaestesia, memory disorders, andepilepsia or other convulsive disorders.

BACKGROUND ART

GABA_(A) receptors for γ-aminobutyric acid (GABA) are the most abundantinhibitory receptors in the mammalian brain. The GABA_(A) receptors arestructurally constituted as macromolecular heteropentameric assemblies(combinations of α, β, and γ/δ protein subunits). Several subtypes ofsuch GABA_(A) receptors have been described by techniques of modemmolecular biology.

Each GABA_(A) receptor complex comprises a chloride ion channel thatcontrols chloride flux across the neuronal membrane, and multiplerecognition sites for small modulatory molecules such asbenzodiazepines, barbiturates, picrotoxin, and certain steroids. WhenGABA interacts with its receptor, the ion channel is opened, chlorideinflux is enhanced, the membrane is hyperpolarized and the cell becomesless responsive to excitatory stimuli. This GABA induced ion current canbe regulated by diverse agents, including agents that interact with thebenzodiazepine receptor or recognition site.

Agents that bind or interact with the modulatory sites on the GABA_(A)receptor complex, such as for example the benzodiazepine receptor, canhave either enhancing effect on the action of GABA, i.e. a positivemodulatory effect of the receptor (agonists, partial agonists), anattenuating effect on the action of GABA, i.e. negative modulation ofthe receptor (inverse agonists, partial inverse agonists), or they canblock the effect of both agonists and inverse agonists by competitiveblock (antagonists or ligands without intrinsic activity).

Agonists generally produce muscle relaxant, hypnotic, sedative,anxiolytic, and/or anticonvulsant effects, while inverse agonistsproduce proconvulsant, antiinebriant, and anxiogenic effects. Compoundswith anxiolytic effects but without or with reduced muscle relaxant,hypnotic and sedative effects are characterised as partial agonists.Partial inverse agonists are considered to be useful as cognitionenhancers.

Numerous compounds belonging to different chemical series of compoundshaving affinity for the benzodiazepine receptors have been synthesizedduring the last three decades. However, although the benzodiazepinereceptor sites are still considered as very attractive biological sitesfor interfering with the CNS to treat various disorders and diseases,then nearly all previously synthesized compounds acting at thesereceptor sites have failed during clinical development because ofunacceptable side effects.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel benzimidazolederivatives and pharmaceutically acceptable acid addition salts thereof,which are useful in the treatment of central nervous system disorders,diseases or ailments, which are responsive to the modulation of theGABA_(A) receptor complex, and in particular the positive modulation ofthe GABA_(A) receptor complex, and having a favorable pharmacodynamicand pharmacokinetic behavior.

Accordingly, the invention provides a chemical compound represented bythe general formula (I):

in which formula (I),

o is 0, 1, 2 or 3;

R¹ represents an alkyl group, a phenyl group, or a monocyclicheterocyclic group, which groups may be substituted one or more timeswith substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl,alkoxy, halogen, trifluoromethyl, cyano, amino, and nitro;

or R¹ represents a cyano group, or a group of the formula -alkyl-CO₂R²,alkenyl-CO₂R², —CO—R², —CO₂(CH₂)_(m)R², or —C(R³)═N—OR², in whichformulas

m is 0, 1, 2 or 3;

R² and R³ independently represents hydrogen, alkyl, alkenyl, alkynyl,phenyl, benzyl, a 5- or 6-membered heterocyclic group, which 5- or6-membered heterocyclic group may optionally be substituted one or moretimes with substituents selected from alkyl, hydroxy, alkoxy, halogen,trifluoromethyl, cyano, amino, or nitro;

or R² and R³ may independently represent a group of the formula—(CH₂)_(q)—NR⁴R⁵, —(CH₂)_(q)—CON(R⁴R⁵), —(CH₂)_(q)—CO₂R⁴, or-alkyl-CO₂R⁴, in which formulas

R⁴ and R⁵ independently represent hydrogen or alkyl; and

q is 0, 1, 2 or 3;

R¹¹ represents a group of the general formula —CO₂—R⁹, wherein

R⁹ represents hydrogen or alkyl, which alkyl may optionally besubstituted with a 5- or 6-membered heterocyclic group, which 5- or6-membered heterocyclic group may optionally be substituted one or moretimes with substituents selected from alkyl, hydroxy, alkoxy, halogen,trifluoromethyl, cyano, amino, or nitro;

or R⁹ may be a 5- or 6-membered heterocyclic group, which 5- or6-membered heterocyclic group may optionally be substituted one or moretimes with substituents selected from alkyl, hydroxy, alkoxy, halogen,trifluoromethyl, cyano, amino, or nitro;

or R⁹ represent a group of the general formula -alkyl-N(R¹⁰R¹²), inwhich formula

R¹⁰ and R¹² independently represent hydrogen or alkyl;

or R¹¹ represents a group of general formula (II):

in which formula (II),

n is 0, 1, 2, or 3;

R′ and R″ each independently represents hydrogen or alkyl; or R′ and R″together with the N atom to which they are attached form a 5- to7-membered heterocyclic ring, which heterocyclic ring may optionallycomprise as a ring member, one oxygen atom, and/or one additionalnitrogen atom, and/or a —CH═CH— chain;

and in which formula the 5- to 7-membered heterocyclic ring formed by R′and R″ may optionally be substituted one ore more times with a group ofthe formula —(CH₂)_(p)X, wherein

p is 0, 1, 2 or 3;

X represents hydrogen, hydroxy, alkyl or alkenyl, which alkyl andalkenyl may optionally be substituted one or more times with a group ofthe formula —CO₂R⁶;

or X represents a group of the formula —CO—R⁶, —CO₂—R⁶, —CON—R⁶R⁷, or—COO—R⁶—NR⁷R⁸, in which formulas

R⁶, R⁷ and R⁸ independently represents hydrogen or alkyl; or R¹¹ mayrepresent a group of the general formula (III):

in which formula (III),

n is 0, 1, 2 or 3;

R′ is hydrogen or alkyl;

R′″ and R″″ together with the atoms to which they are attached form a 5-to 7-membered heterocyclic ring, which heterocyclic ring may optionallycomprise as a ring member, one oxygen atom, and/or one additionalnitrogen atom, and/or a —CH═CH— chain;

and in which formula the 5- to 7-membered heterocyclic ring formed byR′″ and R″″ may optionally be substituted one ore more times with agroup of the formula —(CH₂)_(p)X, wherein

p is 0, 1, 2 or 3;

X represents hydrogen, hydroxy, alkyl or alkenyl, which alkyl andalkenyl may optionally be substituted one or more times with a group ofthe formula —CO₂R⁶;

or X represents a group of the formula —CO—R⁶, —CO₂—R⁶, —CON—R⁶R⁷, or—COO—R⁶—NR⁷R⁸, in which formulas

R⁶, R⁷ and R⁸ independently represents hydrogen or alkyl;

or a pharmaceutically acceptable salt thereof or an oxide thereof.

In another aspect, the invention provides pharmaceutical compositionscomprising the novel benzimidazole compounds of the invention.

Still another object of the present invention is to provide novelmethods of treatment using the novel benzimidazole compounds of theinvention.

A further object of the present invention is to provide a method ofpreparing the novel pharmaceutical compositions of the invention.

Additional objects will be obvious from the following description, andothers will be obvious to a person skilled in the art.

DETAILED DISCLOSURE OF THE INVENTION Benzimidazole Derivatives

In its first aspect the invention provides novel benzimidazolederivatives. The chemical compounds of the invention may becharacterized by the following general formula (I):

in which formula (I),

o is 0, 1, 2 or 3;

R¹ represents an alkyl group, a phenyl group, or a monocyclicheterocyclic group, which groups may be substituted one or more timeswith substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl,alkoxy, halogen, trifluoromethyl, cyano, amino, and nitro;

or R¹ represents a cyano group, or a group of the formula -alkyl-CO₂R²,alkenyl-CO₂R², —CO—R², —CO₂(CH₂)_(m)R², or —C(R³)═N—OR², in whichformulas

m is 0, 1, 2 or 3;

R² and R³ independently represents hydrogen, alkyl, alkenyl, alkynyl,phenyl, benzyl, a 5- or 6-membered heterocyclic group, which 5- or6-membered heterocyclic group may optionally be substituted one or moretimes with substituents selected from alkyl, hydroxy, alkoxy, halogen,trifluoromethyl, cyano, amino, or nitro;

or R² and R³ may independently represent a group of the formula—(CH₂)_(q)—NR⁴R⁵, —(CH₂)_(q)—CON(R⁴R⁵), —(CH₂)_(q)—CO₂R⁴, or-alkyl-CO₂R⁴, in which formulas

R⁴ and R⁵ independently represent hydrogen or alkyl; and q is 0,1,2 or3;

R¹¹ represents a group of the general formula —CO₂—R⁹, wherein

R⁹ represents hydrogen or alkyl, which alkyl may optionally besubstituted with a 5- or 6-membered heterocyclic group, which 5- or6-membered heterocyclic group may optionally be substituted one or moretimes with substituents selected from alkyl, hydroxy, alkoxy, halogen,trifluoromethyl, cyano, amino, or nitro;

or R⁹ may be a 5- or 6-membered heterocyclic group, which 5- or6-membered heterocyclic group may optionally be substituted one or moretimes with substituents selected from alkyl, hydroxy, alkoxy, halogen,trifluoromethyl, cyano, amino, or nitro;

or R⁹ represent a group of the general formula -alkyl-N(R¹⁰R¹²), inwhich formula

R¹⁰ and R¹² independently represent hydrogen or alkyl;

or R¹¹ represents a group of general formula (II):

in which formula (II),

n is 0, 1, 2, or 3;

R′ and R″ each independently represents hydrogen or alkyl;

or R′ and R″ together with the N atom to which they are attached form a5- to 7-membered heterocyclic ring, which heterocyclic ring mayoptionally comprise as a ring member, one oxygen atom, and/or oneadditional nitrogen atom, and/or a —CH═CH— chain; and in which formulathe 5- to 7-membered heterocyclic ring formed by R′ and R″ mayoptionally be substituted one ore more times with a group of the formula—(CH₂)_(p)X, wherein

p is 0, 1, 2 or 3;

X represents hydrogen, hydroxy, alkyl or alkenyl, which alkyl andalkenyl may optionally be substituted one or more times with a group ofthe formula —CO₂R⁶;

or X represents a group of the formula —CO—R⁶, —CO₂—R⁶, —CON—R⁶R⁷,

or —COO—R⁶—NR⁷R⁸, in which formulas

R⁶, R⁷ and R⁸ independently represents hydrogen or alkyl;

or R¹¹ may represent a group of the general formula (III):

in which formula (III),

n is 0, 1, 2 or 3;

R′ is hydrogen or alkyl;

R′″ and R″″ together with the atoms to which they are attached form a 5-to 7-membered heterocyclic ring, which heterocyclic ring may optionallycomprise as a ring member, one oxygen atom, and/or one additionalnitrogen atom, and/or a —CH═CH— chain;

and in which formula the 5- to 7-membered heterocyclic ring formed byR′″ and R″″ may optionally be substituted one ore more times with agroup of the formula —(CH₂)_(p)X, wherein

p is 0, 1, 2 or 3;

X represents hydrogen, hydroxy, alkyl or alkenyl, which alkyl andalkenyl may optionally be substituted one or more times with a group ofthe formula —CO₂R⁶;

or X represents a group of the formula —CO—R⁶, —CO₂—R⁶, —CON—R⁶R⁷, or—COO—R⁶—NR⁷R⁸, in which formulas

R⁶, R⁷ and R⁸ independently represents hydrogen or alkyl

In a preferred embodiment, the chemical compound of the invention ischaracterized by the general formula (I) in wherein o is 0; and

R¹ represents a C₁₋₄-alkyl group, a cyano group, a phenyl group, afuranyl group, a tetrahydrofuranyl group, an isoxazolyl group, or anoxadiazolyl group;

or R¹ represents a C₁₋₄-alkenyl group substituted with CO₂—C₁₋₄-alkyl;

or R¹ represents a group of the formula —CO₂R², in which formula

R² represents hydrogen, a C₁₋₄-alkyl group, or a —C₃₋₅-cyclo—C₁₋₄-alkylgroup, a benzyl group, a picolyl group, a pyrrolidyl group, apyrrolidylmethyl group, or a pyridyl group, which groups may besubstituted with a C₁₋₃-alkyl group;

or R² may represent a group of the formula —(CH₂)_(p) —NR⁴R⁵, or—(CH₂)_(p) —CO—NR⁴R⁵, in which formulas

p is0, 1, or 2;

R⁴ and R⁵ each independently represents hydrogen or a C₁₋₄-alkyl group;

or R² may represent a group of the formula —C(R³)═N—OR⁴, in whichformula

R³ and R⁴ each independently represents hydrogen or a C₁₋₄-alkyl group;

or R¹ represents a group of the formula —C(R³)═N—OR⁴, in which formula

R³ represents hydrogen or a C₁₋₄-alkyl group;

and R⁴ represents hydrogen, a C₁₋₄-alkyl group, or aC₁₋₄-alkyl-CO₂—C₁₋₄-alkyl group.

In a more preferred embodiment, the chemical compound of the inventionis characterized by the general formula (I) in wherein o is 0; and

R¹ is 3-furanyl, 3-tetrahydro-furanyl, 5-isoxazolyl,3-cyclopropyl-1,2,4-oxadiazol-5-yl, —CHNOH, —C(CH₃)NOH, —C(CH₃)NO—CH₃,—C(CH₃)NO—C₂H₅, —C(CH₃)NO-isopropyl, —C(CH₃)NO-t-butyl,—C(CH₃)NO—CH₂CO₂CH₃, —C(CH₃)NO—CH₂CO₂C₂H₅, —CHNO—C(CH₃)₂CO₂CH₃,—C(CH₃)NO—C(CH₃)₂CO₂CH₃, —C(CH₃)NO—C(CH₃)₂CO₂C₂H₅, —C(CH₃)₂CO₂H₅,—C(CH₃)₂CO₂C₂H₅, —CO₂CH₃, —CO₂C₂H₅, —CO₂CH(CH₃)₂, —CO₂(CH₂)₂N(CH₃)₂,—CO₂(CH₂)₂N(C₂H₅)₂, —CO₂—CH₂-cyclopropyl,(N,N-diethyl-carboxamido)methyl, 3-picolyl, or1-methyl-2-pyrrolidyl-methyl.

In another preferred embodiment, the chemical compound of the inventioncharacterized by the general formula (I) in wherein o is 1, 2 or 3; and

R¹ represents a phenyl group, or a group of the formula —CO₂R⁴, in whichformula

R⁴ represents hydrogen or a C₁₋₄-alkyl group.

In a more preferred embodiment, the chemical compound of the inventionis characterized by the general formula (I) in wherein o is 1, 2 or 3;and

R¹ is —CO₂CH₃, —CO₂C₂H₅, —CO₂CH(CH₃)₂, —CO₂CH₂-cyclopropyl, —CHNO—CH₃,—CHNO—C₂H₅, —CHNO—C₃H₇, —CHNO-isopropyl, —C(CH₃)NO—CH₃, —C(CH₃)NO—C₂H₅,—C(CH₃)NO—C₃H₇, —C(CH₃)NO-isopropyl, —C(CH₃)NO—C₄H₉, —C(CH₃)NO-tert.butyl, —CO₂CH₂N(CH₃)₂, —CO₂CH₂N(C₂H₅)₂, 2(dimethyl-amino)ethyl,(N,N-diethyl-carboxamido)-methyl, or 3-picolyl.

In another preferred embodiment, the chemical compound of the inventionis characterized by the general formula (I) in wherein

R¹¹ represents a C₁₋₄-alkyl-oxycarbonyl group, anamino-C₁₋₄-alkyl-oxycarbonyl group, anN—C₁₋₄-alkyl-amino-C₁₋₄-alkyl-oxycarbonyl group, anN,N-di-(C₁₋₄-alkyl)-amino-C₁₋₄-alkyl-oxycarbonyl group, a piperidinylgroup, an oxycarbonyl-piperidinyl group, a pyrrolidinyl group, apyrrolidinyl-C₁₋₄-alkyl group, a piperazinyl group, a morpholinyl group,a homopiperazinyl group, a pyridyl group, a tetrahydropyridyl group, apicolyl group, a oxycarbonyl-picolyl group, which groups may optionallybe substituted one or more times with substituents selected fromC₁₋₄-alkyl, C₁₋₄-alkyl-oxy, C₁₋₄-alkyl-oxycarbonyl,C₁₋₄-alkyl-oxycarbonyl-C₁₋₄-alkyl, C₁₋₄-alkenyl-oxycarbonyl-C₁₋₄-alkyl,C₄-alkenyl-(oxycarbonyl-C₁₋₄-alkyl)₂, acetyl, hydroxy-C₁₋₄-alkyl,carboxamido, N—C₁₋₄-alkyl-carboxamido-C₁₋₄-alkyl, orN,N-di—C₁₋₄-alkyl-carboxamido-C₁₋₄-alkyl.

In a more preferred embodiment, the chemical compound of the inventionis characterized by the general formula (I) in wherein

R¹¹ is 1-piperidinyl, 1-pyrrolidinyl, 4-methyl-1-piperazinyl,1-methyl-3-piperidinyl, (1-methyl-4-piperidinyl)oxycarbonyl,(1-methyl-3-piperidinyl)oxycarbonyl, 2-picolyl-oxycarbonyl,3-picolyl-oxycarbonyl, 4-morpholinyl, 1-acetyl-4-piperazinyl,4-(2-hydroxyethyl)piperazin-1-yl, (1-pyrrolidinyl)methyl,4-methylhomopiperazin-1-yl, 1-methyl-1,2,3,6-tetrahydropyrid-5-yl,4-(N,N-diethyl-carboxamidomethyl)-piperazin-1-yl,4-(N,N-dimethyl-carboxamidomethyl)-piperazin-t -yl,4-(methoxycarbonylmethyl)-1-piperazinyl,4-(ethoxycarbonylmethyl)-1-piperazinyl,4-(t-butoxycarbonylmethyl)-1-piperazinyl,4-(diethylcarboxamido-methyl)piperazin-1-yl,4-(2,2-bis(ethoxycarbonyl)ethenyl)piperazin-1-yl,4-(2-methoxycarbonyl-ethenyl)piperazin-1-yl, methoxycarbonyl,ethoxycarbonyl, 2-amino-ethoxycarbonyl, 2-(N-methylamino)ethoxycarbonyl, or 2-(N,N-dimethylamino)ethoxycarbonyl.

In a most preferred embodiment the chemical compound of the invention is

5-Cyano-1-(3-(1-piperidyl)phenyl)benzimidazole (compound 3a);

5-Cyano-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 3a₂);

5-Cyano-1-(3-(4-methyl-1-piperazinyl)phenyl)benzimidazole (compound3a₃);

5-Cyano-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole (compound3a₄);

5-Cyano-1-(3-(4-morfolinyl)phenyl benzimidazole (compound 3a₅);

5-Formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole oxime (compound 3b₁);

5-Formyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole oxime (compound 3b₂):

5-Formyl-1-(3-(4-methyl-1-piperazinyl)phenyl)benzimidazole oxime(compound 3b₃);

5-Formyl-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole oxime(compound 3b₄);

5-Formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole 0-isopropyl oxime(compound 3c);

5-Formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole 0-methyl oxime(compound 3d);

5-Acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole oxime(compound 3e₁);

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenylbenzimidazoleoxime (compound 3e₂);

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenylbenzimidazoleO-ethyl oxime (compound 3f₁);

5-Acetyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole O-ethyl oxime(compound 3k2);

5-Acetyl-1-(3-(1-pyrrolidinylmethyl)phenyl)benzimidazole O-ethyl oxime(compound 3f₃);

5-Acetyl-1-(3-(4-methylhomopiperazin-1-yl)benzimidazole O-ethyl oxime(compound 3f₄);

5-Acetyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole O-ethyl oxime(compound 3f₅);

5-Acetyl-1-(3-(1-piperidinyl)phenyl)benzimidazole O-ethyl oxime(compound 3f₆);

5-Acetyl-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole O-ethyl oxime(compound 3f₇);

5-Acetyl-1-(3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl)benzimidazoleO-ethyl oxime (compound 3f₈);

5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole O-isopropyloxime (compound ³g₁);

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazoleO-isopropyl oxime (compound 3g₂);

5-Acetyl-1-(3-(4-acetylpiperazin-1-yl)phenyl)benzimidazole O-isopropyloxime (compound 3g₃);

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazoleO-t-butyl oxime (compound 3h);

5-(3-Furanyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(compound 3i₁);

5-(3-Furanyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole(compound 3i₂);

5-(3-Furanyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazole(compound 3i₃);

5-(3-Furanyl)-1-(3-(4-(diethylcarboxamidomethyl)piperazin-1-yl)phenyl)benzimidazole(compound 3i₄);

5-phenyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound3j₁);

5-phenyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound3j₂);

5-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole(compound 3k);

5-t-Butyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound31);

5-(Ethoxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole(compound 4a₁);

5-(Ethoxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(compound 4a₂);

5-(Ethoxycarbonyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazole(compound 4a₃);

5-(Ethoxycarbonyl)-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole(compound 4a₄);

5-(Ethoxycarbonyl)-1-(3-(4-(methoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole(compound 4a₅);

5-(Ethoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole(compound 4a₆);

5-(2-(Ethoxycarbonyl)ethenyl)-1-(3-(1-piperidyl)phenyl)benzimidazole(compound 4b₁);

5-(2-(Ethoxycarbonyl)ethenyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(compound 4b₂);

5-(2-(Ethoxycarbonyl)ethenyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole(compound 4b₃);

5-(2-(Methoxycarbonyl)ethenyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(compound 4c₁);

5-(2-(Methoxycarbonyl)ethenyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole(compound 4c₂);

5-(Methoxycarbonyl)-1-(3-(1-acetylpiperazin-3-yl)phenyl)benzimidazole(compound 4d₁);

5-(Methoxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(compound 4d₂);

4-(Methoxycarbonyl)-l-(3-(4-methoxycarbonylmethyl)piperazin-1-yl)benzimidazole (compound4d₃);

5-(Methoxycarbonyl)-1-(3-(4-(diethylcarboxamidemethyl)piperazin-1-yl)phenyl)-benzimidazole(compound 4d₄);

5-(Methoxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole (compound4d₅);

5-(i-Propyloxycarbonyl)-1-(3-(1-piperidinyl)phenyl)benzimidazole(compound 4e₁);

5-(i-Propyloxycarbonyl)-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole(compound 4e₂);

5-(i-Propyloxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(compound 4e₃);

5-(i-Propyloxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole(compound 4e₄);

5-(Cyclopropylmethyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole(compound 4f;

5-(Benzyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole(compound 4g);

5-(3-Picolyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole(compound 4h);

5-(2-((Dimethylamino)ethyl)oxycarbonyl)-1-(3-(1-acetylpiperazin-4-yl)phenyl)-benzimidazole(compound 4i);

5-((2-(Dimethylamino)ethyl)oxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole(compound 4j);

5-((N,N-Diethylcarboxamido)methyloxycarbonyl)-1-(3-(4-ethoxycarbonylmethyl)-piperazin-1-yl)phenyl)benzimidazole(compound 4k₁);

5-((N,N-diethylcarboxamido)-methyloxycarbonyl)-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole(compound 4k₂);

5-(Methoxycarbonylmethyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(compound 4l₁);

5-(Ethoxycarbonylmethyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(compound 4l₂);

5-(Methoxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole (compound4l₃);

5-(Ethoxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole (compound4l₄);

5-((1-Methylpyrrolidin-2-yl)methoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)-piperazin-1-yl)phenyl)benzimidazole(compound 4m);

5-Acetyl-1-(3-(1-methyl-4-piperidyloxycarbonyl)phenyl)benzimidazoleO-isopropyl oxime (compound 5a₁);

5-Acetyl-1-(3-(1-methyl-3-piperidyloxycarbonyl)phenyl)benzimidazoleO-i-propyl oxime (compound 5a₂);

5-Acetyl-1-(3-(2-picolyloxycarbonyl)phenyl)benzimidazole O-i-propyloxime (compound 5a₃);

5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazoleO-(ethoxycarbonyl-methyl) oxime (compound 5b₁);

5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazoleO-(methoxycarbonylmethyl) oxime (compound 5b₂);

5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazoleO-(methoxycarbonyl-(dimethyl)methyl) oxime (compound 5b₃);

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazoleO-(methoxy-carbonylmethyl) oxime (compound 5c₁);

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazolO-(ethoxy-carbonylmethyl) oxime (compound 5c₂);

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazoleO-(ethoxy-carbonyl(dimethyl)methyl) oxime (compound 5c₃);

5-Acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazoleoxime (compound 5d₁);

5-Acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperidin-1-yl)phenyl)benzimidazoleO-ethyl oxime (compound 5d₂);

5-Acetyl-1-(3-(t-acetylpiperazin-4-yl)phenyl)benzimidazoleO-(methoxycarbonyl-(dimethyl)methyl) oxime (compound 5e₁);

5-Acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazoleO-(methoxycarbonyl-methyl) oxime (compound 5e₂);

5-Acetyl-1-(3-(4-morfolinyl)phenyl)benzimidazoleO-(methoxycarbonylmethyl) oxime (compound 5e₃);

5-Acetyl-1-(3-(4-(methoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazoleO-i-propyl oxime (compound 5f₁);

5-acetyl-1-(3-(4-(2,2-bis(ethoxycarbonyl)ethenyl)piperazin-1-yl)phenyl)benzimidazoleO-i-propyl oxime (compound 5f₂);

5-Formyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazoleO-(methoxycarbonyl-(dimethyl)methyl) oxime (compound 5g₁);

5-Formyl-1-(3-(4-morfolinyl)phenyl)benzimidazole(methoxycarbonyl)dimethyl)-methyl) oxime (compound 5g₂);

5-(5-Isoxazolyl)-1-(3-(methoxycarbonyl)phenyl)benzimidazole (compound6a₁);

5-(5-Isoxazolyl)-1-(3-ethoxycarbonyl)phenyl benzimidazole (compound6a₂); 1-(3-Ethoxycarbonyl)phenyl-5-phenylbenzimidazole (compound 6b₁);

5-phenyl-1-(3-(4-ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole(compound 6b₂);

5-phenyl-1-(3-(2-picolyloxycarbonyl)phenyl)benzimidazole (compound 6b₃);

5-phenyl-1-(3-(3-picolyloxycarbonyl)phenyl)benzimidazole (compound 6b₄);

5-phenyl-1-(3-(1-methylpiperidin-3-yloxycarbonyl)phenyl)benzimidazole(compound 6b₅);

5-phenyl-1-(3-((1-methylpiperidin-4-yl)oxycarbonyl)phenyl)benzimidazole(compound 6b₆);

5-(3-furanyl)-1-(3-(ethoxycarbonyl)phenyl)benzimidazole (compound 6c₁);

5-(3-Tetrahydrofuranyl)-1-(3-(ethoxycarbonyl)phenyl)benzimidazole(compound 6c₂);

5-(3-Furanyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole(compound 6c₃);

5-(3-Furanyl)-1-(3-(4-(t-butoxycarbonyl)piperazin-1-yl)phenyl)benzimidazole(compound 6c₄);

5-(3-Furanyl)-1-(3-(4-(methoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole(compound 6c₅);

5-(3-Furanyl)-1-(3-(4-(2,2-bis(ethoxycarbonyl)ethenyl)piperazin-1-yl)phenyl)benzimidazole(compound 6c₆);

5-(3-Furanyl)-1-(3-(4-(2-(methoxycarbonyl)ethenyl)piperazin-1-yl)phenyl)benzimidazole(compound 6c₇);

5-(3-Furanyl)-l-(3-(2-(dimethylamino)ethyloxycarbonyl)phenyl)benzimidazole (compound6c₈);

5-Acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]-benzimidazole(compound 7); or

5-Acetyl-1-[3-(1-methylpiperidin-3-yl)phenyl]-benzimidazole (compound9); or a pharmaceutically acceptable salt thereof, or an oxide thereof.

Definition of Substituents

In the context of this invention halogen represents fluorine, chlorine,bromine and iodine.

In the context of this invention alkyl designates a straight chain or abranched chain containing of from one to eight carbon atoms(C₁-C₈-alkyl), including but not limited to methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl, or acyclic alkyl containing of from three to seven carbon atoms (C₃-C₇cycloalkyl), including but not limited to cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. In a preferred embodiment of this inventionalkyl represents a C₁-C₄ alkyl, preferably a C₁₋₃-alkyl, most preferredmethyl, ethyl, propyl, isopropyl or t-butyl.

In the context of this invention alkenyl designates a group containingof from two to six carbon atoms (C₂-C₆ alkenyl), including at least onedouble bond. The chain may be straight or branched. In a preferredembodiment, the alkenyl group is ethenyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl, or 3-butenyl.

In the context of this invention alkynyl designates a group containingof from two to six carbon atoms (C₂-C₆ alkynyl), including at least onetriple bond. The chain may be straight or branched. In a preferredembodiment, the alkenyl group is ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, or 3-butynyl.

In the context of this invention amino represents NH₂, NH-alkyl, orN-(alkyl)₂, wherein alkyl is as defined above.

In the context of this invention cycloalkyl-alkyl designates acycloalkyl as defined above which is attached to an alkyl as alsodefined above, e.g. cyclopropylmethyl.

The alifatic cyclic rings formed by R′ and R″ or R″ and R′″ includes butare not limited to piperidinyl, tetrahydropyridinyl,tetrahydropyrimidinyl, hexahydropyrimidinyl, pyrrolidinyl,homopiperazinyl, morpholinyl, isoxazolidinyl, oxazolindinyl,piperazinyl, perhydroazepinyl, and perhydroazepinyl.

In the context of this invention aryl designates an aromatichydrocarbon, such as phenyl or naphthyl.

In the context of this invention a monocyclic heteroaryl designates a 5-or 6-membered heterocyclic monocyclic group. Preferred monocyclicheteroaryl group includes oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl,1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, 1-imidazolyl,2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl,4-pyridazinyl, 2-pyrazinyl,l-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl.

In the context of this invention 5- or 6-membered ring containing atleast one heteroatom includes but are not limited to furanyl,tetrahydrofuranyl, pyrrolyl, pyrrolidyl, imidazolyl, oxadiazolyl,pyridyl, thienyl, isooxazolyl, pyrimidyl, pyrazole,

In the context of this invention alkyl-oxy (alkoxy) designates analkyl-O-where alkyl is as defined above.

In the context of this invention alkyl-oxycarbonyl (alkoxycarbonyl)designates an alkyl-O—CO— where alkyl is as defined above.

Steric Isomers

Some of the chemical compounds of the present invention exist in (+) and(−) forms as well as in racemic forms.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof,with an optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptical active matrix. Racemic compounds of the present invention canthus be resolved into their optical antipodes, e.g., by fractionalcrystallisation of d- or I- (tartrates, mandelates, orcamphorsulphonate) salts for example.

The chemical compounds of the present invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe in art. Such methods include those described by Jaques J, Collet A,& Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Moreover, being oximes, the chemical compounds of the invention mayexist in two forms, syn- and anti-form (Z- and E-form), depending on thearrangement of the substituents around the —C═N— double bond. A chemicalcompound of the present invention may thus be the syn- or the anti-form(Z- and E-form), or it may be a mixture hereof.

Pharmaceutically Acceptable Salts

The novel benzimidazole derivatives of the invention may be provided inany form suitable for the intended administration. Suitable formsinclude pharmaceutically (i.e. physiologically) acceptable salts.

Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts such as the hydrochloride, hydrobromide,phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate,maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate,benzenesulfonate, methanesulfonate, stearate, succinate, glutamate,glycollate, toluene-p-sulphonate, formate, malonate,naphthalene-2-sulphonate, salicylate and the acetate. Such salts areformed by procedures well known in the art.

Other acids such as oxalic acid, while not in themselvespharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a chemical compound of theinvention and its pharmaceutically acceptable acid addition salt.

Metal salts of a chemical compound of the invention includes alkalimetal salts, such as the sodium salt, of a chemical compound of theinvention containing a carboxy group.

The chemical compound of the invention may be provided in solved ordissolved form together with a pharmaceutically acceptable solvents suchas water, ethanol and the like. In general, solved forms are consideredequivalent to dissolved forms for the purposes of this invention.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thechemical compound of the invention. While a chemical compound of theinvention for use in therapy may be administered in the form of the rawchemical compound, it is preferred to introduce the active ingredient,optionally in the form of a physiologically acceptable salt in apharmaceutical composition together with one or more excipients,carriers and/or diluents.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention or apharmaceutically acceptable salt or derivative thereof together with oneor more pharmaceutically acceptable carriers therefor and, optionally,other therapeutic and/or prophylactic ingredients. The carrier(s) mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

Pharmaceutical compositions those suitable for oral, rectal, nasal,topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administration,or in a form suitable for administration by inhalation or insufflation.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, in the form of suppositories forrectal administration; or in the form of sterile injectable solutionsfor parenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. Compositions containingten (10) amilligrams of active ingredient or, more broadly, 0.1 to onehundred (100) milligrams, per tablet, are accordingly suitablerepresentative unit dosage forms.

The chemical compound of the present invention can be administrated in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the chemical compoundaccording to the invention may be formulated as ointments, creams orlotions, or as a transdermal patch. Ointments and creams may, forexample, be formulated with an aqueous or oily base with the addition ofsuitable thickening and/or gelling agents. Lotions may be formulatedwith an aqueous or oily base and will in general also contain one ormore emulsifying agents, stabilising agents, dispersing agents,suspending agents, thickening agents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerin or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

Biological Activity and Methods of Treatment

4-aminobytyric acid (GABA) is the major inhibitory neurotransmitterwhich has been shown to act throughout both the central and peripheralnervous system. At present two types of GABA receptors are known, theGABA_(A) and the GABA_(B) receptors. Recent molecular biology hasdemonstrated that the GABA_(A) receptors can be subdivided into numeroussubreceptors consistant with the selective and or partialpharmacological effects observed with certain benzodiazepine receptorligands as opposed to the unselective effects observed for the classicalbenzodiazepine receptor ligands such as for example diazepam.

Activation of GABA receptors leads to alternations in membrane potential(hyperpolarization),. The GABA_(A) receptors are associated withchloride influx through its associated and integrated chloride channel,whereas GABA_(B) receptor activation indirectly alters potassium andcalcium channels as well as modifies second messenger production. TheGABA_(A) recognition sites can be activated by GABA, muscimol, andisoguvacine for example, but not by GABA_(B) agonists such as forexample baclofen. The modulatory GABA_(A) recognition site at thebenzodiazepine receptor sites can be selectively radiolabelled with³H-flunitrazepam.

The affinity of various potential ligands for the benzodiazepinereceptor sites can thus be evaluated by estimating the ability of testcompounds to displace ³H-flunitrazepam.

The compounds of the present invention may be useful for the treatmentof disorders or diseases of a living animal body due to their modulatoryeffect on the benzodiazepine recognition site of the GABA_(A) receptorcomplex. This property make the compounds of this invention extremelyuseful as muscle relaxants and in the treatment of convulsions, anxiety,sleep disorders, anaestesia, memory disorders as well as other disorderssensitive to modulation of the GABA_(A) receptor.

Accordingly, the compounds of the present invention may be administeredto a subject, including a human, in need of treatment, alleviation, orelimination of a disorder or disease associated with GABA_(A) receptors.This includes especially convulsions, anxiety, sleep disorders,anaestesia, and memory disorders.

It is at present contemplated that a suitable dosage range is of fromabout 0.01 to about 100 mg per day, more preferred of from about 0.1 toabout 50 mg per day, most preferred of from about 0.1 to about 30 mg perday, dependent, however, upon the exact mode of administration, the formin which it is administered, the indication towards which theadministration is directed, the subject involved and the body weight ofthe subject involved, and further the preference and experience of thephysician or veterinarian in charge.

Methods of Preparation

The novel benzimidazole derivatives of the invention may be prepared byconventional methods of chemical synthesis, e.g. those described in theworking examples. The starting materials for the processes described inthe present application are known or may readily be prepared byconventional methods from commercially available chemicals.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

EXAMPLES

The invention is further illustrated with reference to the followingexamples which are not intended to be in any way limiting to the scopeof the invention as claimed.

The compounds of this invention represented by the following generalformula

were prepared as outlined in the following scheme (Scheme 1):

The starting materials (1 and 2) used for this preparation are listed inTables 1-2, below.

TABLE 1 Compounds 1a-1i

Compound Method of preparation No. R₁ X (Example) 1a CN Cl Commerciallyavailable 1b CH₃CO F 1 1c CO₂Et Cl 2 1d 3-furanyl F 3 1e phenyl F 3 1ft-Bu F 4 1g I F 3 1h CO₂CH₂CON(Et)₂ Cl 22 1i CH₂COOH F 23

TABLE 2 Compounds 2a-2p

Com- Method of pound preparation No. R₂ (Example) 2a 1-piperidinyl 5 2b1-pyrrolidinyl 5 2c 4-methyl-1-piperazinyl 5 2d 1-acetyl-4-piperazinyl 62e 4-(ethoxycarbonylmethyl)-1-piperazinyl 6 2f4-((N,N-diethylcarboxamido)methyl)-1- 6 piperazinyl 2g1-(t-butoxycarbonyl)-4-piperazinyl 7 2h 1-methyl-4-homopiperazinyl 7 2i(1-pyrrolidinyl)methyl 8 2j 1-methyl-3-piperidinyl 9 2k4-(2-hydroxyethyl)-1-piperazinyl 6 2l4-(methoxycarbonylmethyl)-1-piperazinyl 6 2m4-(2,2-bis(ethoxycarbonyl)ethenyl)piperazin-1-yl 6 2n4-(2-(methoxycarbonyl)ethenyl)piperazin-1-yl 6 2o 4-morfolinyl 5 2p3-pyridyl 9a

TABLE 3 Compounds 3a-l

Met. of Comp. M.p. Starting Prep. No. R₁ R₂ (° C.) Mater. (Ex.) 3a₁ CN1-piperidinyl 106-8 2a/1a 10 3a₂ CN 1-pyrrolidinyl 171-2 2b/1a 10 3a₃ CN4-methyl-1-piperazinyl 177-9 2c/1a 10 3a₄* CN 1-methyl-3-piperidinyl158-60 2j/1a 10 3a₅ CN 4-morfolinyl 163-5 2o/1a 10 3b₁ CHNOH1-piperidinyl 213-4 3a₁ 11 3b₂ CHNOH 1-pyrrolidinyl 242-4 3a₂ 11 3b₃CHNOH 4-methyl-1-piperazinyl 224-7 3a₃ 11 3b₄ CHNOH1-methyl-3-piperidinyl 214-8 3a₄ 11 3c CHNOiPr 1-piperidinyl 127-8 3a₂11 3d CHNOMe 1-piperidinyl 107-8 3a₂ 11 3e₁ CH₃CNOH1-acetyl-4-piperazinyl 240-1 2d/1b 12 3e₂ CH₃CNOH 4-(2-hydroxyethyl)-193-5 2k/1b 12 piperazin-1-yl 3f₁* CH₃CNOEt 4-(2-hydroxyethyl)- oil2k/1b 12 piperazin-1-yl 3f₂* CH₃CNOEt 4-methyl-1-piperazinyl 62-3 2c/1b12 3f₃* CH₃CNOEt (1-pyrrolidinyl)methyl 158-62 2i/1b 12 3f₄* CH₃CNOEt4-methylhomopiperazin- 147-51 2h/1b 12 1-yl 3f₅ CH₃CNOEt 1-pyrrolidinyl118-20 2b/1b 12 3f₆ CH₃CNOEt 1-piperidinyl 88-9 2a/1b 12 3f₇* CH₃CNOEt1-methylpiperidin-3-yl 112-14 2j/1b 12 3f₈* CH₃CNOEt 1-methyl-1,2,3,6-227-233 2p/1b 12a tetrahydropyrid-5-yl 3g₁* CH₃CNOiPr1-methylpiperidin-3-yl 48-55 2j/1b 12 3g₂* CH₃CNOiPr 4-(2-hydroxyethyl)-165-9 2k/1b 12 piperazin-1-yl 3g₃* CH₃CNOiPr 1-acetyl-4-piperazinyl160-3 2d/1b 12 3h CH₃CNOt-Bu 4-(2-hydroxyethyl)- oil 2k/1b 12piperazin-1-yl 3i₁ 3-furanyl 4-methylpiperazin-1-yl 129-30 2c/1g 13 3i₂3-furanyl 1-methylpiperidin-3-yl 96-7 2j/1g 13 3i₃ 3-furanyl4-(2-hydroxyethyl)- 137-40 2k/1g 13 piperazin-1-yl 3i₄ 3-furanyl4-(N,N-diethyl- 107-9 2f/1g 13 carboxamidomethyl)- piperazin-1-yl 3j₁phenyl 4-methylpiperazin-1-yl 131-2 2c/1g 13 3j₂ phenyl1-methylpiperidin-3-yl 42-4 2j/1g 13 3k* 3-cyclopropyl-1-methylpiperidin-3-yl 184-90 4a₁ 14 1,2,4-oxadiazol- 5-yl 3l* t-butyl1-methylpiperidin-3-yl ˜200 2j/1f 15 *isolated as the hydrochloride.

TABLE 4 Compounds 4a-m

Met. Comp. Start. Pre. No. n m R₁ R₂ M.p. (° C.) Mat. (Ex) 4a₁* 0 0ethyl 1-methylpiperidin-3-yl hygroscop. 2j/1c 16 4a₂ 0 0 ethyl4-methylpiperazin-1-yl 86-7 2c/1c 16 4a₃* 0 0 ethyl 4-(2-hydroxyethyl)-233-6 2k/1c 16 piperazin-1-yl 4a₄ 0 0 ethyl 1-acetylpiperazin-4-yl 155-62d/1c 16 4a₅* 0 0 ethyl 4-(methoxy- 185-6 2l/1c 16 carbonylmethyl)-1-piprazinyl 4a₆* 0 0 ethyl 4-(ethoxy- 196-200 2e/1c 16 carbonylmethyl)-1-piperazinyl 4b₁ 1 2 ethyl 1-piperidinyl 85-7 3a₁ 17 4b₂ 1 2 ethyl4-methylpiperazin-1-yl 133-4 3a₃ 17 4b₃ 1 2 ethyl 4-morfolinyl 197-2003a₅ 17 4c₁ 1 2 methyl 4-methylpiperazin-1-yl 138-40 3a₃ 17 4c₂ 1 2methyl 4-morfolinyl 137-9 3a₅ 17 4d₁ 0 0 methyl 1-acetyl-4-piperazinyl189-91 2d/1j 18 4d₂ 0 0 methyl 4-methyl-1-piperazinyl 119-21 2c/1j 184d₃ 0 0 methyl 4-(methoxy- oil 2l/1j 18 carbonylmethyl)- piperazin-1-yl4d₄ 0 0 methyl 4-(diethyl- oil 2f/1j 18 carboxamido-methyl)-piperazin-1-yl 4d₅ 0 0 methyl 4-morfolinyl 150-2 2o/1j 18 4e₁ 0 0i-propyl 1-piperidinyl 160-61 2a/1k 19 4e₂ 0 0 i-propyl 1-pyrrolidinyl170-72 2b/1k 19 4e₃ 0 0 i-propyl 4-methylpiperazinyl-1- 110-11 2c/1k 19yl 4e₄ 0 0 i-propyl 4-morfolinyl 173-4 2o/1k 19 4f 0 0 cyclopropyl-1-methylpiperidin-3-yl 111-13 4a₁ 20 methyl 4g* 0 0 benzyl1-methylpiperidin-3-yl “90” 4a₁ 20 4h 0 0 3-picolyl1-methylpiperidin-3-yl oil 4a₁ 20 4i 0 0 2-(dimethyl-1-acetylpiperazin-4-yl 101-3 2d 21 amino)ethyl 4j 0 0 2-(dimethyl-4-(ethoxy- oil 2e 21 amino)ethyl carbonylmethyl)- piperazin-1-yl 4k₁ 0 0(N,N-diethyl- 4-(ethoxy- 93-4 2e/1h 22 carboxamido)- carbonylmethyl)-methyl piperazin-1-yl 4k₂ 0 0 (N,N-diethyl- 1-acetylpiperazin-4-yl oil2d/1h 22 carboxamido)- methyl 4l₁* 2 1 methyl 4-methylpiperazin-1-yl140-42 2c/1i 24 4l₂* 2 1 ethyl 4-methylpiperazin-1-yl 180-82 2c/1i 244l₃* 2 1 methyl 4-morfolinyl 164-5 2o/1i 24 4l₄* 2 1 ethyl 4-morfolinyl168-9 2o/1i 24 4m 0 0 1-methyl-2- 4-(ethoxy- oil 2e 25 pyrrolidyl-carbonylmethyl)- methyl piperazin-1-yl *isolated as the hydrochloride.

TABLE 5 Compounds 5a-g

Method of Comp. M.p. Prep. No. R₁ R₂ R₃ (° C.) (Ex.) 5a₁ CH₃ i-Pr(1-methyl-4-piperidyl)- 106-7 26 oxycarbonyl 5a₂ CH₃ i-Pr(1-methyl-3-piperidyl)- 83-4 26 oxycarbonyl 5a₃ CH₃ i-Pr(2-picolyl)-oxycarbonyl 104-6 26 5b₁* CH₃ CH₂CO₂Et 1-methyl-3-piperidyl73-5 27 5b₂ CH₃ CH₂CO₂Me 1-methyl-3-piperidyl 104-6 27 5b₃ CH₃C(CH₃)₂CO₂Me 1-methyl-3-piperidyl 113-6 27 5c₁ CH₃ CH₂CO₂Me4-(2-hydroxyethyl)- 117-9 28 piperazin-1-yl 5c₂* CH₃ CH₂CO₂Et4-(2-hydroxyethyl)- oil 28 piperazin-1-yl 5c₃ CH₃ C(CH₃)₂CO₂Et4-(2-hydroxyethyl)- oil 28 piperazin-1-yl 5d₁ CH₃ H4-(ethoxycarbonylmethyl)- 154-6 29 piperazin-1-yl 5d₂ CH₃ ethyl4-(ethoxycarbonylmethyl)- 119-20 29 piperazin-1-yl 5e₁ CH₃ C(CH₃)₂CO₂Me1-acetylpiperazin-4-yl 119-20 30 5e₂ CH₃ CH₂CO₂Me 1-acetylpiperazin-4-yl137-9 30 5e₃ CH₃ CH₂CO₂Me 4-morfolinyl 149-50 30 5f₁ CH₃ i-propyl4-(methoxy- 120-2 31 carbonylmethyl)-piperazin- 1-yl 5f₂ CH₃ i-propyl4-(2,2-bis- 128-9 31 (ethoxycarbonyl)- ethenyl)piperazin-1-yl 5g₁* HC(CH₃)₂CO₂Me 4-methylpiperazin-1-yl 199-201 32 5g₂* H C(CH₃)₂CO₂Me4-morfolinyl 175-7 32 *isolated as the hydrochloride.

TABLE 6 Compounds 6a-c

Method Comp. Start. of Prep. No. R₁ R₂ M.p. (° C.) Mat. (Ex.) 6a₁ 5-CO₂Me 190-1 33 isoxazolyl 6a₂ 5- CO₂Et 156-7 33 isoxazolyl 6b₁ phenylCO₂Et 122-3 1e 34 6b₂ phenyl 4-(ethoxycarbonylmethyl)- 121-2 2e/1e 34piperazin-1-yl 6b₃ phenyl 2-picolyloxycarbonyl 149-50 6b₁ 35 6b₄* phenyl3-picolyloxycarbonyl 195-7 6b₁ 35 6b₅* phenyl (1-methyl-3- 180-91 6b₁ 35piperidyl)oxycarbonyl 6b₆* phenyl (1-methyl-4-piperidyl)- 187-8 6b₁ 35oxycarbonyl 6c₁ 3-furanyl CO₂Et 87-9 1d 36 6c₂* 3-tetra- CO₂Et 168-71 1d36 hydrofuranyl 6c₃ 3-furanyl 4-(ethoxycarbonylmethyl)- 110-2 1d/2e 36piperazin-1-yl 6c₄ 3-furanyl 4-(t-butoxycarbonyl)-piperazin- 162-4 1d/2g36 1-yl 6c₅ 3-furanyl 4-(methoxycarbonylmethyl)- 124-5 1d/2l 36piperazin-1-yl 6c₆ 3-furanyl 4-(2,2-bis(ethoxycarbonyl)- 97-102 1d/2m 36ethenyl)-piperazin-1-yl 6c₇ 3-furanyl 4-(2-(methoxycarbonyl)- 131-31d/2n 36 ethenyl)-piperazin-1-yl 6c₈* 3-furanyl 2-(dimethylamino)- 200-21d 36 ethoxycarbonyl *isolated as the hydrochloride.

Example 1 Preparatory Example

4-Fluoro-3-nitroacetophenone (1b): Concentrated sulfuric acid (200 ml)is cooled to 5° C. 4-Fluoroacetophenone (20 ml, 0.16 mol) is addedkeeping the 5 temperature below 10° C. The mixture is cooled to 0-5° C.and potassium nitrate (25 g, 0.25 mol) is added portionwise over 2 hourskeeping the temperature within this range. Following the addition themixture is stirred in the cold for additionally 2 hours. The mixture ispoured on ice (600 g) and the crude product is filtered off.Column-chromatographic purification on silica gel using a mixture ofethyl acetate and petroleum ether (1:9) as the eluent affords pure 1(18.2 g, 60%). Mp 48-49° C.

Example 2 Preparatory Example

Ethyl 4-chloro-3-nitrobenzoate (1c): 4-chloro-3-nitrobenzoic acid (40.0g, 0.2 mol) was refluxed in thionyl chloride (150 ml) for 6 hours. Aftercooling toluene (50 ml) was added and the mixture was evaporated todryness. Abs. ethanol (500 ml) was added to the cooled residue, and theresulting mixture was refluxed overnight. The excess of ethanol wasremoved under reduced pressure and the product crystallized uponaddition of aqueous sodium bicarbonate (1M). Yield: 42.5 g (93%).

Example 3 Preparatory Example

4-Fluoro-1-iodo-3-nitrobenzene (1g): A vigorously stirred suspension of4-fluoro-3-nitroaniline (25 g, 0.16 mol) in conc. hydrochloric acid (125ml) was cooled to −15° C. A solution of sodium nitrite (12.1 g, 0.18mol) in water (25 ml) was added drop-wise keeping the temperature at−15° C. Following the addition the mixture was stirred for 15 minwhereafter a solution of potassium iodide (33.4 g, 0.2 mol) in water (65ml) was added over 45 min. At the end of the addition the mixture wasstirred for additionally 30 min at ambient temperature. Aqueous sodiumsulfite (1M) was added to remove iodine and the resulting mixture wasextracted thrice with diethyl ether. The combined extracts weresuccessively washed with ice-cold aqueous sodium hydroxide (1M) andbrine, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel, using a mixture of ethyl acetate and petroleum ether (1:9 v/v) asthe eluent, to yield the desired product (30.3 g, 71%) as a yellowishoil.

3-(4-Fluoro-3-nitrophenyl)furan (1d): A mixture of 1 g (25 g, 94 mmol),3-furanyl-boronic acid (13.1 g, 117 mmol), potassium carbonate (38.8 g,281 mmol), 1,3-propanediol (33.8 ml, 468 mmol) andtetrakis(triphenylphosphine)-palladium(0) (0.5 g) in a mixture of1,2-dimethoxyethane passed through Al₂O₃ to remove peroxides (100 ml)and water (50 ml) was heated to reflux under nitrogen for 1 hour. Theprogress of the reaction was monitored by TLC using a mixture of ethylacetate and petroleum ether (1:9 v/v) as the mobile phase. The mixturewas poured into ice-water (500 ml). The precipitate was filtered off,washed with water and dissolved in ethyl acetate (200 ml). This solutionwas washed with cold 1 M HCl (3×100 ml) and brine. The organic phase wasdried over Na₂SO₄ and evaporated to dryness to leave a crude product(100%). The crude product was dissolved in a mixture of dichlorometaneand petroleum ether (1:1, v/v) and filtered through a short column (1.59 silica gel per gram crude product). The column was washed with theabove mixture (20 ml per gram crude product). The solvent was removedunder reduced pressure and the residue was recrystallized (60° C.→0° C.)from 2-propanol (4 ml per gram residue).

Yield: 80%. M.p. 74.3-74.9° C. ¹H NMR (DMSO-d₆): 7.11 ppm (s, 1H), 7.64ppm (dd, 1H), 7.80 ppm (s, 1H), 8.06 ppm (m, 1H), 8.36 ppm (dd, 1H),8.39 ppm (s, 1H).

4-Fluoro-3-nitrobiphenyl (1e) was prepared analogously from 1g andphenylboronic acid.

Example 4 Preparatory Example

4-Fluoro-3-nitro-t-butylbenzene (1f): To a cold (5° C.) suspension of4-t-butylaniline in a mixture of conc. hydrochloric acid (25 ml) andwater (25 ml) was added a solution of sodium nitrite (7.6 g, 0.11 mol)in water (10 ml) keeping the temperature at 5-7° C. At the end of theaddition, the mixture was stirred for additionally 15 min, whereafter asolution of sodium tetrafluoroborate (15.4 g, 0.14 mol) in water (30 ml)was added dropwise, maintaining the temperature at 5-8° C. After another15 min at 5° C. the diazonium salt was filtered off, dried with suctionand washed with diethyl ether (yield: 21 g). The diazonium salt wasdecomposed by gentle heating to 120° C. on an oil-bath. The product wasdistilled off and collected to yield if (11.2, 73.5%).

Example 5 Preparatory Example

3-(1-piperidyl)aniline (2a): A mixture of 3-fluoronitrobenzene (10.0 g,70.9 mmol) and piperidine (14 ml, 141 mmol) was stirred at 110° C. for 3days. After cooling water (200 ml) was added and the mixture wasextracted with dichloromethane (3×100 ml). The combined organic extractswere washed with saturated aqueous sodium carbonate, dried over sodiumsulfate and evaporated to dryness to leave 1-(3-nitrophenyl)piperidine(13.7 g, 93%) as an oil. This oil was dissolved in ethanol (150 ml) andwas hydrogenated at ambient pressure using palladium on activated carbonas the catalyst to yield 2a (11.7 g, 100%) as an oil.

The following compounds were prepared analogously;

3-(1-pyrrolidinyl)aniline (2b);

3-(4-methyl-1-piperazinyl)aniline (2c); and

3-(4-morfolinyl)aniline (2o).

Example 6 Preparatory Example

3-(1-acetylpiperazin-4-yl)aniline (2d): A mixture of3-fluoronitrobenzene (10.7 ml, 0.1 mol) and piperazine (43 g, 0.5 mol)in anhydrous NMP was heated to 115° C. for 2 days. After cooling themixture was poured into water (200 ml) and extracted with ethyl acetate(3×50 ml). The combined organic extracts were washed with brine, driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column-chromatography on silica gel with a mixture ofdichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v) as theeluent to yield 1-(3-nitrophenyl)piperazine (17.2 g, 83%). Thisintermediate was acetylated with acetic acid anhydride (yield: 90%) andhydrogenated in methanol at ambient pressure using Pd (5% on activatedcarbon) as the catalyst to yield 2d (11.9 g, 74%) as off-white crystals.

In analogy herewith alkylation of 1-(3-nitrophenyl)piperazine with ethyl2-bromoacetate, N,N-diethyl chloroacetamide, 2-bromoethanol, methyl2-bromoacetate, diethyl ethoxymethylenmalonate and methylpropiolatefollowed by hydrogenation afforded respectively:

Ethyl 2-(4-(3-aminophenyl)piperazin-1-yl)acetate (2e);

N, N-diethyl 2-(4-(3-nitrophenyl)piperazin-1-yl)acetamide (2f);

3-(4-(2-hydroxyethyl)piperazin-1-yl)aniline (2k);

Methyl 2-(4-(3-aminophenyl)piperazin-1-yl)acetate (21);

Diethyl (4-(3-aminophenyl)piperazin-1-yl))methylenmalonate (2m); and

Methyl 2-(4-(3-aminophenyl)piperazin-1-yl)acrylate (2n).

Example 7 Preparatory Example

3-(1-(t-butoxycarbonyl)piperazin-4-yl)aniline (2g): A mixture oftert-butyl 1-piperazinecarboxylate (4 g, 21.5 mmol) and3-fluoronitrobenzene (2.3 ml, 21.5 mmol) in anhydrous NMP (5 ml) washeated to 120° C. for 3 days. After cooling water (25 ml) was added andthe mixture was extracted with ethyl acetate (2×10 ml). The organicextract was dried over sodium sulfate and the solvent was removed underreduced pressure. The residue was purified by column-chromatographyusing successively petroleum ether and a mixture of ethyl acetate andpetroleum ether (1:1 v/v) as the eluents. Yield of t-butyl4-(3-nitrophenyl)-1-piperazinecarboxylate: 1.34 g (20%). Thisintermediate was quantitatively hydrogenated to 2g in ethanol at ambientpressure using Pd (5% on activated carbon) as the catalyst.

The following compound was prepared analogously:

3-(1-methyl-4-homopiperazinyl)aniline (2h).

Example 8 Preparatory Example

3-((1-pyrrolidinyl)methyl)aniline (21): To a solution of3-nitrobenzylbromide (3 g, 13.9 mmol) in anhydrous THF (30 ml) was addeda solution of pyrrolidine (2.3 ml, 27.8 mmol) in anhydrous THF (10 ml)dropwise with stirring. Following the addition the mixture was stirredat ambient temperature overnight. The reaction mixture was filtered. Thefilter cake was washed with a small volume of anhydrous THF and thefiltrate was concentrated to leave the intermediate1-(3-nitrobenzyl)pyrrolidine as an oil. This oil was dissolved inmethanol (50 ml) and three equivalents of both ammonium chloride andsodium sulfide nonahydrate were added. The mixture was heated to refluxfor 2 hours. After cooling the mixture was filtered. The filtercake waswashed with methanol and the filtrate was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and dried oversodium sulfate. Filtration and evaporation of solvent left 2iquantitatively as yellow crystals.

Example 9 Preparatory Example

3-(1-methyl-3-piperidinyl)aniline (2j): A mixture of3-nitrophenylboronic acid (50 g, 0.3 mol), 3-bromopyridine (48 ml, 0.5mol), potassium carbonate (207 g, 1.5 mol), 1,3-propanediol (107 ml, 1.5mol) and tetrakis(triphenylphosphine)palladium(0) (0.5 g) in a mixtureof water (200 ml) and dimethoxyethane (400 ml) was stirred in a nitrogenatmosphere at 80° C. for 3 hours. After cooling the dimethoxyethane wasremoved under reduced pressure and the residue was stirred withadditionally 200 ml water overnight. The precipitate was filtered offand extracted with aqueous hydrochloric acid (4M, 300 ml). The extractwas rendered alkaline by addition of aqueous sodium hydroxide (12M). Theproduct was filtered off, washed with water and dried with suction toyield 3-(3-nitrophenyl)pyridine (50.6 g, 84%).

3-(3-nitrophenyl)pyridine (50 g, 0.25 mol) was added portion-wise withstirring to dimethyl sulfate (125 ml). The mixture was stirred atambient temperature for 24 hours, during which time additional dimethylsulfate was added (2×50 ml). At the end of the reaction diethyl ether(400 ml) was added, and the mixture was stirred in the cold for 2 hours.The precipitate was filtered off and washed several times with diethylether. Finally, the precipitate was stirred in pyridine (100 ml) at 45°C. for 30 min. THF (250 ml) was added. Stirring was continued foradditionally 30 min whereafter the product was filtered off, washed withdiethyl ether and dried to yield 1-methyl-3-(3-nitrophenyl)pyridiniummethyl sulfate (66.6 g, 82%).

The above salt (66 g, 0.2 mol) was dissolved in methanol (750 ml) andsodium borohydride (11.4 g, 0.3 mol) was added in portions. At the endof the addition the mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was partitioned betweenwater and diethyl ether. The organic phase was dried over sodium sulfateand concentrated under reduced pressure. This concentrate was dissolvedin ethanol (500 ml) and hydrogenated at ambient pressure using Pd (5% Pdon activated carbon) as the catalyst. Yield of 2j: 24.2 g (64%).

3-(3-Pyridyl)aniline (2p): A mixture of diethyl 3-pyridylborane (16.3 g,0.11 mol), 3-bromoaniline (12.2 ml, 0.11 mol), potassium carbonate (45.8g, 0.33 mol) and tetrakis(triphenylphosphine)palladium(0) (80 mg) in amixture of water (40 ml) and dimethoxyethane (80 ml) is heated to 80° C.under a stream of nitrogen over night. After cooling the mixture isdiluted with water and ethyl acetate and filtered through a flutedfilterpaper. The layers are separated. The aqueous layer is extractedonce with ethyl acetate. The combined organic phases are dried oversodium sulfate and concentrated under reduced pressure. The residue isdissolved in ethanol. Water is added and the mixture is evaporated todryness. This residue crystallizes upon trituration with ice-cold water.The crystals are collected, dried and washed with petroleum ether toafford pure 2p (16.3 g, 87%). Mp 75-76° C.

Example 10

5-Cyano-1-(3-(1-piperidyl)phenyl)benzimidazole (3at): A mixture of4-chlor-3-nitrobenzonitril (5.0 g, 27.4 mmol), 2a (4.8 g, 27.4 mmol) andtriethylamine (3.8 ml, 27.4 ml) in anhydrous NMP (5 ml) was heated withstirring to 120° C. under a stream of nitrogen overnight. After coolingthe mixture was poured into water (50 ml). The crude product wasfiltered off, washed with water and dried with suction. Treatment withactivated carbon in refluxing ethanol yielded pureN-(3-(1-piperidyl)phenyl)-4-cyano-2-nitroanilin (6.24 g, 71%).

This intermediate product (6.17 g, 19.1 mmol) was hydrogenated inethanol at ambient pressure using Pd (5% on activated carbon) as thecatalyst to yield the corresponding diamine (5.6 g, 100%), which wastreated with formic acid (25 ml) at 80° C. for 1 hour. After cooling themixture was poured into water (100 ml) and rendered alkaline by additionof saturated aqueous sodium carbonate. The product was filtered off andpurified by treatment with activated carbon in refluxing ethanolfollowed by column-chromatography on silica gel using a mixture of ethylacetate and petroleum ether (1:1 v/v) as the eluent. Yield of 3a₁: 4.4 g(70%). M.p. 106-108° C.

The following compounds were prepared analogously:

5-Cyano-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (3a₂). M.p. 171-172°C.;

5-Cyano-1-(3-(4-methyl-1-piperazinyl)phenyl)benzimidazole (3a₃). M.p.177-179° C.;

5-Cyano-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole, hydrochloride(3a₄). M.p. 158-160° C.; and

5-Cyano-1-(3-(4-morfolinyl)phenyl benzimidazole (3a₅). M.p. 163-165° C.

Example 11

5-Formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole oxime (3b₁): To asolution of 3a₁ (3.83 g, 12.9 mmol) in a mixture of formic acid (45 ml)and water (15 ml) was added Raney Ni (2.14 g, slurry in water). Themixture was refluxed with stirring for 3 hours. After cooling themixture was filtered through celite and the filtrate was evaporated todryness. The residue was partitioned between ethyl acetate and aqueoussodium bicarbonate (1M). The organic phase was dried over sodium sulfateand concentrated under reduced pressure. The concentrate was elutedthrough a short silica gel column with ethyl acetate. Evaporation of thesolvent left 5-formyl-1-(3-(1-piperidinyl)phenyl)-benzimidazole (3.86 g,100%) as an oil. This oil was dissolved in refluxing ethanol (15 ml).Hydroxyl amine hydrochloride (2.64 g, 38.0 mmol) and triethylamine (1.70ml) was added and reflux was continued for 5 hours. The cooled mixturewas rendered basic by addition of triethylamine. Water was added and thepricipitate was filtered off, washed with water and dried to yield 3b₁(2.89 g, 70%). M.p. 213-214° C.

The following compounds were prepared analogously, using the appropriatehydroxylamines:

5-Formyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole oxime (3b₂). M.p.242-244° C.;

5-Formyl-1-(3-(4-methyl-1-piperazinyl)phenyl)benzimidazole oxime (3b₃).M.p. 224-227° C.;

5-Formyl-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole oxime (3b₄).M.p. 241-218° C.;

5-Formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole O-isorronyl oxime(3c). M.p. 127-128° C.; and

5-Formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole O-methyl oxime (3d).M.p. 107-108° C.

Example 12

5-Acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole oxime (3e₁):A mixture of 1b (0.75 g, 4.1 mmol) and 2d (0.9 g, 4.1 mmol) in anhydrousNMP (2 ml) was heated to 80° C. overnight under a stream of nitrogen.After cooling water (20 ml) was added and the mixture was extracted withdichloromethane. The organic extract was dried over sodium sulfate andthe solvent was removed under reduced pressure. The residue was purifiedby column-chromatography on silica gel using ethyl acetate as the eluentto yield 4-acetyl-N-(3-(1-acetylpiperazin-4-yl)phenyl)-2-nitroaniline asan oil.

This oil was dissolved in ethanol (25 ml) and was hydrogenated atambient pressure using Pd (5% on activated carbon) as the catalyst. Theresulting mixture was filtered through celite and the solvent wasremoved under reduced pressure. To the residue was added formic acid (5ml) and the mixture was heated to 80° C. for 1 hour. After cooling waterwas added and the product was extracted with ethyl acetate.Column-chromatographic work-up on silica gel using a mixture of ethylacetate and methanol (9:1) as the eluent yielded5-acetyl-1-(3-(1-acetylpiperazinyl-4-yl)phenyl)benzimidazole (0.53 g,36%). M.p. 112-114° C.

This product was treated with hydroxylamine hydrochloride in ethanol asdescribed in Example 11 to yield 3e, (90%). M.p. 240-242° C.

The following compounds were prepared analogously:

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenylbenzimidazoleoxime (3e₂). M.p. 193-195° C.;

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenylbenzimidazoleO-ethyl oxime (3f₁), ¹H-NMR (CDCl_(3, 500) MHz): 1.44 ppm (t, 3H), 2.43ppm (s, 3H), 2.82 ppm (t, 2H), 2.92 ppm (m, 4H), 3.47 ppm (m, 4H), 3.83ppm (t, 2H), 4.36 ppm (q, 2H), 7.07 ppm (m, 3H), 7.53 ppm (t, 1H), 7.59ppm (d, 1H), 7.86 ppm (d, 1H), 8.15 ppm (s, 1H), 8.20 ppm (s, 1H);

5-Acetyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole O-ethyloxime, hydrochloride (3f₂). M.p. 62-63° C. (oily crystals);

5-Acetyl-1-(3-(1-pyrrolidinylmethyl)phenyl)benzimidazole O-ethyl oxime,hydrochloride (3f₃). M.p. 158-162° C.;

5-Acetyl-1-(3-(4-methylhomopiperazin-1-yl)benzimidazole O-ethyl oxime,hydrochloride (3f₄). M.p. 147-151° C.;

5-Acetyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole O-ethyl oxime (3f₅).M.p. 18-120° C.;

5-Acetyl-1-(3-(1-piperidinyl)phenyl)benzimidazole O-ethyl oxime (3f₆).M.p. 8-89° C.;

5-acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole O-ethyl oximehyrochloride (3f₇). M.p. 112-114° C.;

5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole O-isopropyloxime, hydrochloride (3g₁). M.p. 48-55° C. ¹H-NMR (CDCl₃, 500 MHz): 1.37ppm (d, 6H), 1.75 ppm (qd, 1H), 2.08 ppm (d, 1H), 2.23 ppm (d, 1H), 2.34ppm (s, 3H), 2.54 ppm (m, 1H), 2.80 ppm (m, 1H), 2.87 ppm (s+m, 4H),3.64 ppm (t, 2h), 3.80 ppm (m, 1H), 4 ppm (hept., 1H), 7.43 ppm (d, 2H),7.51 ppm (m, 3H), 7.61 ppm (t, 1H), 7.86 ppm 1H), 8.13 ppm (s, 1H), 8.47ppm (broad, 1H);

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazoleO-isopropyl oxime, hydrochloride (3g₂). M.p. 165-169° C.;

5-Acetyl-1-(3-(4-acetylpiperazin-1-yl)phenyl)benzimidazole O-isopropyloxime, hydrochloride (3g₁). M.p. 160-163° C.; and

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazoleO-t-butyl oxime (3h). ¹ H-NMR (CDCl₃, 500 MHz): 1.34 ppm (s, 9H), 2.25ppm (s, 3H), 2.86 ppm (broad, 2H), 2.98 ppm (broad, 4H), 3.47 ppm(broad, 4H), 3.82 (broad, 2H), 6.97 ppm (m, 3H), 7.44 ppm (m, 2H), 7.77ppm (d, 1H), 8.06 ppm (s, 2H).

Example 12a

5-Acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazoleO-ethyl oxime (3f₈):

4-Acetyl-N-(3-(3-pyridyl)phenyl-2-nitroaniline: A mixture of 1b fromExample 1 (5 g, 27.3 mmol) and 2p from Example 9a (4.62 g, 27.2mmol) indry N-methyl-2-pyrrolidone (10 ml) is stirred at 40-50° C. over night.The resulting solid reaction mixture is suspended in ice-water andrendered alkaline by addition of aqueous sodium carbonate (1M). Theproduct is filtered off, washed with water and dried to yield 7.68 g 4(85%). Mp 112-113° C.

4-Acetyl-N-[3-(1-methylpyrid-3-ylium)phenyl]-2-nitroanilinemethylsulfate (5):

4-Acetyl-N-[3-(3-pyridyl)phenyl]-2-nitroaniline (4) (3.68 g, 11.05 mmol)in dimethyl sulfate (7.5 ml) was stirred at ambient temperature for 15min. Diethyl ether was added and the mixture was stirred foradditionally 30 min. The product was filtered off and dried to yield4-acetyl-N-[3-(1-methylpyrid-3-ylium)phenyl]-2-nitroanilinemethylsulfate (5) (4.9 g, 96.6%). Mp 118-125° C.

4-Acetyl-N-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]-2-nitroaniline(6):

To a suspension of4-acetyl-N-[3-(1-methylpyrid-3-ylium)phenyl]-2-nitroanilinemethylsulfate (5) (4.9 g, 10.7 mmol) in methanol (50 ml) sodiumborohydride (0.6 g, 16 mmol) was added portionwise with stirring. Theresulting solution was stirred for 1 hour whereafter the solvent wasremoved by evaporation. The residue was partitioned between water andethyl acetate. The organic phase was dried over sodium sulfate,concentrated under reduced pressure and purified by columnchromatography on silica gel using a mixture of dichloromethane,methanol and acetone (4:1:1 v/v) as the eluent. Yield: 2.1 g (56%).

5-Acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazole(7):

A mixture of4-acetyl-N-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]-2-nitroaniline(5) (1 g, 3 mmol), sodium sulfide nonahydrate (4.32 g, 18 mmol) andammonium chloride (0.96 g, 18 mmol) in methanol (50 ml) was heated toreflux over night. The solvent was removed under reduced pressure andthe residue was partitioned between ethyl acetate and water. The organicphase was dried over sodium sulfate and concentrated to leave an oil(m/e: 321) which was stirred in formic acid (10 ml) at 80° C. for 4hours. The resulting mixture was concentrated under reduced pressure.The residue was dissolved in water and filtered. The filtrate wasrendered alkaline by addition of solid sodium carbonate and extractedwith ethyl acetate. This extract was dried over sodium sulfate.Evaporation of the solvent left5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazole(7) as an oil. Yield: 0.5 g (50%), m/e: 331. A minor sample of this oilwas dissolved in ethanol and precipitated as the hydrochloride byaddition of hydrogen chloride in diethyl ether. Mp 227-233° C.

5-Acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazoleO-ethyl oxime (3f₈):

To a solution of5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazole(7) (free base from above) in ethanol was added O-ethyl hydroxylaminehydrochloride. The mixture was heated to reflux for 1.5 hours whereafterthe solvent was removed under reduced pressure. The residue wastriturated with a mixture of diethyl ether and ethanol leaving5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazoleO-ethyl oxime (3f₈) as hygroscopic crystals. Mp 138-143° C., m/e 374.

Example 12b

5-Acetyl-1-[3-(1-methylpiperidin-3-yl)phenyl]benzimidazole (9):

To a solution of4-acetyl-N-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]-2-nitroaniline(6, Ex. 12a) (1 g, 3 mmol) in ethanol (50 ml) was added a catalyticamount of palladium on charcoal and the mixture was hydrogenated atambient pressure over night. The reaction mixture was filtered throughcelite and the filtrate was concentrated under reduced pressure. To thisconcentrate formic acid (10 ml) was added and the resulting solution wasstirred at 80° C. over night. Excess formic acid was removed byevaporation. The residue was dissolved in water and rendered alkaline byaddition of solid sodium carbonate. Extraction with ethyl acetate andtreatment of the extract with activated carbon in ethanol afforded5-acetyl-1-[3-(1-methylpiperidin-3-yl)phenyl]-benzimidazole (9) (0.5 g,50%) as an oil. m/e 333.

Example 13

5-(3-Furanyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (31i₁):A mixture of 1g (1.4 g, 5.2 mmol) and 2c (1.0 g, 5.2 mmol) in anhydrousNMP (5 ml) was heated to 80° C. under a stream of nitrogen overnight.The mixture was poured into ice-water (50 ml) and rendered alkaline byaddition of saturated aqueous sodium carbonate. The precipitate wasfiltered off and purified by column-chromatography on silica gel using amixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v)as 15 the eluent. Yield of4-iodo-2-nitro-N-(3-(4-methylpiperazin-1-yl)phenyl)aniline: 1.32 g(58%).

To a solution of the above product (1.3 g, 2.97 mmol) in a mixture ofdimethoxyethane (20 ml) and water (10 ml) was added 3-furanylboronicacid (0.5 g, 4.45 mmol), potassium carbonate (1.23 g, 8.91 mmol),tetrakis(triphenylphosphine)palladium(0) (70 mg) and 1,3-propandiol(1.07 ml, 14.8 mmol). The resulting mixture was stirred under a streamof nitrogen at 80° C. for 6 hours. After cooling the mixture wasfiltered. The filtrate was diluted with water (50 ml) and extracted withethyl acetate. The combined organic extracts were washed with brine,dried over sodium sulfate and evaporated to dryness to leave4-(3-furanyl)-2-nitro-N-(3-(4-methylpiperazin-1-yl)phenyl)aniline (0.95g, 85%) as a red oil.

This oil was hydrogenated at ambient pressure in ethanol using Pd (5% onactivated carbon) as the catalyst to yield2-amino-4-(3-furanyl)—N-(3-(4-methylpiperazin-1-yl)phenyl)aniline (0.6g, 69%), which was treated with refluxing formic acid (5 ml) for 1 hour.After cooling the solution was poured into ice-water (25 ml) and aqueoussodium hydroxide (10M) was added to basic reaction. Extraction withethyl acetate followed by chromatographic work-up on silica gel with amixture of ethyl acetate and methanol (9:1 v/v) as the eluent left pure3i₁ (0.23 g, 41%). M.p. 129-130° C.

The following compounds were prepared analogously:

5-(3-Furanyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (3i2).M.p. 96-97° C.;

5-(3-Furanyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazole(3i₃). M.p. 137-140° C.;

5-(3-Furanyl)-1-(3-(4-(N,N-diethylcarboxamidomethyl)piperazin-1-yl)phenyl)benzimidazole(3i4). M.p. 107-109° C.;

5-phenyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (3j₁). M.p.131-132° C.

5-phenyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (3j₂). M.p.42-44° C.;

In case of 3j₁ and 3j₂ phenylboronic acid was employed.

Example 14

5-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole,hydrochloride (3k): To a solution of sodium (0.1 g, 4 mmol) in anhydrousethanol (10 ml) was added 4a₁ (see example 16) (0.36 g, 1 mmol) andcyclopropylcarboxamide oxime and the mixture was heated to refluxovernight. After removal of the solvent the residue was partitionedbetween water and ethyl acetate. The organic phase was dried over sodiumsulfate and concentrated under reduced pressure. The productprecipitated upon addition of a solution of anhydrous hydrogen chloridein diethyl ether. Yield of 3k: 0.2 g (46%). M.p. 184-190° C.

Example 15

5-t-Butyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole,hydrochloride (3l): A mixture of 1f (1.26 g, 6.9 mmol) and 2j (1.22 g,6.4 mmol) in anhydrous NMP (2 ml) was heated with stirring in a nitrogenatmosphere to 80° C. overnight. Aqueous sodium carbonate was added tothe cooled reaction mixture, and the resulting mixture was extractedwith ethyl acetate. The organic phase was concentrated and purified bycolumn-chromatography on silica gel using a mixture of ethyl acetate andmethanol (9:1 v/v) as the eluent. Yield of4-t-butyl-N-(3-(1-methylpiperidin-3-yl)phenyl)-2-nitroanilin (0.32 g,14%) as an oil. This oil was dissolved in ethanol (15 ml) and washydrogenated at ambient pressure using Pd (5% on activated carbon) asthe catalyst to yield the corresponding phenylenediamine quantitatively.To a solution of this2-amino-4-t-butyl-N-(3-(1-methylpiperidin-3-yl)phenyl)aniline in THF (5ml) was added triethyl orthoformate (0.3 ml, 1.8 mmol) and a catalyticamount of pTSA. The resulting mixture was heated to reflux overnight. Tothe cooled solution aqueous sodium carbonate (1M) was added and themixture was extracted with ethyl acetate. The organic extract was driedover sodium sulfate and evaporated to dryness. The residue was treatedwith a solution of anhygrous hydrogenchloride in diethyl ether to leave31 (0.21 g, 63%) as a hygroscopic solid. M.p. approx. 200° C. (collapsesat 70° C.). m/e: 347.

Example 16

5-(Ethoxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole,hydrochloride (4a₁): A mixture of 1c (5.7 g, 25 mmol), 2j (3.8 g, 20mmol) and potassium carbonate (3.45 g, 25 mmol) was heated to 70° C.under a stream of nitrogen. The resulting melt was stirred at 70° C.overnight. The reaction mixture was partitioned between water and ethylacetate and the organic phase was extracted with diluted hydrochloricacid (4M). The aqueous phase was rendered alkaline by addition ofaqueous sodium hydroxide (4M) and extracted with ethyl acetate. Theorganic phase was dried over sodium sulfate and the solvent was removedunder reduced pressure to leave ethyl4-(3-(1-methylpiperidin-3-yl)phenylamino)-3-nitrobenzoate (7.5 g, 98%)as an oil.

The above oil was dissolved in ethanol (150 ml) and was hydrogenated atambient pressure using Pd (5% on activated carbon) as the catalyst. Theresulting phenylendiamine was treated with formic acid (25 ml) at 80° C.for 4 hours. Hereafter the excess formic acid was removed byevaporation. The residue was partitioned between aqueous sodiumhydroxide (1M) and ethyl acetate. The organic phase was concentrated andpurified by column-chromatography on silica gel using a mixture ofdichloromethane, methanol and acetone (4:1:1 v/v/v) as the eluent.Evaporation of the solvent and treatment of the residue with a solutionof anhydrous hydrogen chloride in diethyl ether (2M) left (4a₁)5-(ethoxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole,hydrochloride (2.8 g, 35%) as a hygroscopic solid. ¹H-NMR (DMSO-d₆, 500MHz): 1.43 ppm (t, 3H), 1.47 ppm (m, 1H), 1.83 ppm (m, 2H), 2.00 ppm (m,2H), 2.06 ppm (t, 1H), 2.34 ppm (s, 3H), 2.98 ppm (m, 3H), 4.40 ppm (q,3H), 7.37 ppm (m, 3H), 7.50 ppm (m, 2H), 8.05 ppm (d, 1H), 8.17 ppm (s,1H), 8.58 ppm (s, 1H).

The following compounds were prepared analogously:

5-(Ethoxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(4a₂). M.p. 86-87° C.;

5-(Ethoxycarbonyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazole,hydrochloride (4a₃). M.p. 233-236° C.;

5-(Ethoxycarbonyl)-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole(4a₄). M.p. 155-156° C.;

5-(Ethoxycarbonyl)-1-(3-(4-(methoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole,hydrochloride (4a₅). M.p. 185-186° C.; and

5-(Ethoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole,hydrochloride (4a₆). M.p. 196-200° C.

Example 17

5-(2-(Ethoxycarbonyl)ethenyl)-1-(3-(1-piperidyl)phenyl)benzimidazole(4b₁): To a suspension of sodiumhydride (70 mg, 60% dispersion inmineral oil) in anhydrous toluene (5 ml) was added triethylphosphonoacetate (0.33 ml, 1.64 mmol), keeping the temperature at 30-35°C. Following the addition, stirring was continued until a clear solutionhad formed (approx. 15 min). A solution of5-formyl-1-(3-(1-piperidinyl)phenyl) benzimidazole (0.5 g, 1.64 mmol.Prepared as described in Example 11) in anhydrous toluene (2 ml) wasadded dropwise at 20-30° C. Following the addition the mixture wasstirred at ambient temperature for 15 min and then at 60-65° C. foradditional 15 min. Stirring was continued at ambient temperatureovernight. The reaction mixture was decanted, leaving a rubber-likeresidue, which was extracted several times with toluene. The combineddecantates were washed with water, dried over sodium sulfate andevaporated to dryness. The residue was triturated with petroleum etherto yield 4b₁ (0.38 g, 61%). M.p. 85-87° C.

The following compounds were prepared analogously:

5-(2-(Ethoxycarbonyl)ethenyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(4b₂). M.p. 133-134° C.;

5-(2-(Ethoxycarbonyl)ethenyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole(4b₃). M.p. 197-200° C.;

5-(2-(Methoxycarbonyl)ethenyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(4c₁). M.p. 138-140° C.; and

5-(2-(Methoxycarbonyl)ethenyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole(4c2). M.p. 137-139° C.

For the two latter preparations methyl diethyl phosphono acetate wasemployed.

Example 18

5-(Methoxycarbonyl)-1-(3-(1-acetylpiperazin-3-yl)phenyl)benzimidazole(4d₁): To a solution of methyl 4-chloro-3-nitrobenzoate (2.0 g, 9.28mmol) in anhydrous NMP (5 ml) was added 2d (2.03 g, 9.28 mmol) andtriethylamine (1.3 ml, 9.28 mmol). The mixture was heated with stirringto 80° C. overnight. The cooled solution was poured into ice-water (50ml) and the resulting mixture was extracted with ethyl acetate (3×10ml). The combined organic extracts were washed with water, dried oversodium sulfate and evaporated to dryness. The residue was trituratedwith petroleum ether to yield methyl4-(3-(1-acetylpiperazin-4-yl)anilino)-3-nitrobenzoate (3.14 g, 85%) asred crystals.

This intermediate product was dissolved in methanol (50 ml) and washydrogenated at ambient pressure using Pd (5% on activated carbon) asthe catalyst to yield the corresponding diamino compound (2.8 g, 96%).

To a solution of this diamine in THF (50 ml) was added triethylorthoformate (2.5 ml, 15.2 mmol) and a catalytic amount of pTSA. Themixture was heated to reflux for 1 hour. After cooling the solvent wasremoved by evaporation and the residue was partitioned between aqueoussodium carbonate (1M) and ethyl acetate. The organic phase was driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by column-chromatography on silica gel using a mixture ofethyl acetate and methanol (9:1 v/v) as the eluent. Yield of 4d₁: 5.52(53%). M.p. 189-191° C.

The following compounds were prepared analogously:

5-(Methoxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(4d₂). M.p. 119-121° C.;

4-(Methoxycarbonyl)-1-(3-(4-methoxycarbonylmethyl)piperazin-1-yl)benzimidazole(4d₃). ¹H-NMR (CDCl₃, 500 MHz): 2.90 ppm (broad, 4H), 3.35 ppm (broad,6H), 3.70 ppm (s, 3H), 3.90 ppm (s, 3H), 6.91 ppm (m, 2H), 6.95 ppm (d,1H), 7.39 ppm (t, 1H), 7.48 ppm (d, 1H), 7.99 ppm (d, 1H), 8.11 ppm (s,1H), 8.51 ppm (s, 1H);

5-(Methoxycarbonyl)-1-(3-(4-(N,N-diethylcarboxamidemethyl)piperazin-1-yl)phenyl)-benzimidazole(4d₄). ¹H-NMR (CDCl₃, 500 MHz): 1.18 ppm (t, 3H), 1.26 ppm (t, 3H), 2.90(broad, 4H), 3.42 ppm (m, 1H), 3.99 ppm (s, 3H), 6.98 ppm (superimposedd+s, 2H), 7.04 ppm (d, 1H), 7.56 ppm (d, 1H), 8.07 ppm (d, ₁H), 8.20 ppm(s, 1H), ppm (s, 1H); and

5-(Methoxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole (4d₅). M.p.150-152° C.

Example 19

5-(i-Propyloxycarbonyl)-1-(3-(1-piperidinyl)phenyl)benzimidazole (4e₁):To a mixture of isopropyl 4-chloro-3-nitrobenzoate (3.0 g, 12.3 mmol)and 2a (2.16 g, 12.3 mmol) in anhydrous NMP (5 ml) was addedtriethylamine (1.71 ml, 12.3 mmol) and the mixture was stirred at 80° C.under a stream of nitrogen overnight. The cooled mixture was partitionedbetween ethyl acetate and water. The organic phase was extracted withdiluted hydrochloric acid (4M). The aqueous extract was renderedalkaline by addition of aqueous sodium hydroxide (12M) and extractedwith ethyl acetate. This organic extract was dried over sodium sulfateand concentrated under reduced pressure. The residue waschromatographied on silica gel using a mixture of ethyl acetate andpetroleum ether (1:1 v/v) as the eluent to yield isopropyl3-nitro-4-(3-(1-piperidinyl)anilino)benzoate (2.55 g, 54%) as a red oil.This intermediate product was dissolved in ethanol (50 ml) hydrogenatedat ambient pressure. The resulting diamine was treated with formic acid(25 ml) at 80° C. for 1 hour. The reaction mixture was poured into water(100 ml) and rendered alkaline by addition of aqueous sodium hydroxide(10M). The crude product was filtered off, washed with water and dried.Purification was achieved by treatment with activated carbon inrefluxing 2-propanol followed by trituration with diethyl ether. Yieldof 4e₁: 1.27 g (53%). M.p. 160-161° C.

The following compounds were prepared analogously:

5-(Methoxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(4d₂). M.p. 119-121° G; 304-(Methoxycarbonyl)-1-(3-(4-methoxycarbonylmethyl)piperazin-1-yl)benzimidazole(4d₃). ¹H-NMR (CDCl₃, 500 MHz): 2.90 ppm (broad, 4H), 3.35 ppm (broad,6H), 3.70 ppm (s, 3H), 3.90 ppm (s, 3H), 6.91 ppm (m, 2H), 6.95 ppm (d,1H), 7.39 ppm (t, 1H), 7.48 ppm (d, 1H), 7.99 ppm (d, 1H), 8.11 ppm (s,1H), 8.51 ppm (s, 1H);

5-(Methoxycarbonyl)-1-(3-(4-(N,N-diethylcarboxamidemethyl)piperazin-1-yl)phenyl)-benzimidazole(4d₄). ¹H-NMR (CDCl₃, 500 MHz): 1.18 ppm (t, 3H), 1.26 ppm (t, 3H), 2.90(broad, 4H), 3.42 ppm (m, 1H), 3.99 ppm (s,; 3H), 6.98 ppm (superimposedd+s, 2H), 7.04 ppm (d, 1H), 7.56 ppm (d, 1H), 8.07 ppm (d, 1H), 8.20 ppm(s, 1H), 8.60 ppm (s, 1H); and

5-(Methoxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole (4d₅). M.p.150-152° C.

Example 19

5-(i-Propyloxycarbonyl)-1-(3-(1-piperidinyl)phenyl)benzimidazole (4e₁):To a mixture of isopropyl 4-chloro-3-nitrobenzoate (3.0 g, 12.3 mmol)and 2a (2.16 g, 12.3 mmol) in anhydrous NMP (5 ml) was addedtriethylamine (1.71 ml, 12.3 mmol) and the mixture was stirred at 80° C.under a stream of nitrogen overnight. The cooled mixture was partitionedbetween ethyl acetate and water. The organic phase was extracted withdiluted hydrochloric acid (4M). The aqueous extract was renderedalkaline by addition of aqueous sodium hydroxide (12M) and extractedwith ethyl acetate. This organic extract was dried over sodium sulfateand concentrated under reduced pressure. The residue waschromatographied on silica gel using a mixture of ethyl acetate andpetroleum ether (1:1 v/v) as the eluent to yield isopropyl3-nitro-4-(3-(1-piperidinyl)anilino)benzoate (2.55 g, 54%) as a red oil.This intermediate product was dissolved in ethanol (50 ml) hydrogenatedat ambient pressure. The resulting diamine was treated with formic acid(25 ml) at 80° C. for 1 hour. The reaction mixture was poured into water(100 ml) and rendered alkaline by addition of aqueous sodium hydroxide(10M). The crude product was filtered off, washed with water and dried.Purification was achieved by treatment with activated carbon inrefluxing 2-propanol followed by trituration with diethyl ether. Yieldof 4e₁: 1.27 g (53%). M.p. 160-161° C.

The following compounds were prepared analogously:

5—(i-Propyloxycarbonyl)-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (4e₂).M.p. 170-172° C.;

5-(i-Propyloxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole(4e₃). M.p. 110-111° C.; and

5—(i-Propyloxycarbonyl)-1-(3-4-morfolinyl)phenyl)benzimidazole (4e₄).M.p. 173-174° C.

Example 20

5-(Cyclopropylmethyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole(4f): To a solution of 4a₁ (1.5 g, 3.8 mmol) in ethanol (10 ml) wasadded aqueous potassium hydroxide (10 ml, 2M) and the mixture was heatedto reflux for 2 hours. The ethanol was removed under reduced pressure,and the residue was neutralized by addition of acetic acid. Theresulting amino acid was filtered off and dried. This product wassuspended in toluene (100 ml). Thionylchloride (3 ml) was added, and themixture was heated to 80° C. for 4 hours. The cooled mixture wasevaporated to dryness, and the residue was suspended in anhydrous THF(60 ml).

To a part of the above suspension (20 ml) was added cyclopropylmethanol(0.8 ml, 10 mmol) and the mixture was stirred at room temperature for 5days. The solvent was removed by evaporation and the residue waspartitioned between aqueous sodium hydroxide (1M) and ethyl acetate. Theorganic phase was dried over sodium sulfate and evaporated to dryness.The residue was triturated with petroleum ether to yield 4f (30 mg, 7%).M.p. 111-113° C.

The following compounds were prepared analogously:

5-(Benzyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole,hydrochloride (4 g). M.p. collapse at 90° C. M/e: 425; and

5-(3-Picolyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole(4h). ¹H-NMR (CDCl₃, 500 MHz): 1.45 ppm (m, 1H), 1.8 ppm (broad, 2H),2.1 ppm (broad, 3H), 2.4 ppm (broad, 3H), 3.0 ppm (broad, 3H), 5.36 ppm(s, 2H), 7.3 ppm (several signals, 4H), 7.45 ppm (“t”, 2H), 7.77 ppm (d,1H), 8.01 ppm (d, 1H), 8.12 pp (s, 1H), 8.55 ppm (d, 1H), 8.57 ppm (s,1H), 8.69 ppm (s, 1H).

Example 21

5-(2-((Dimethylamino)ethyl)oxycarbonyl)-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole(4i): To a solution of 2-(dimethylamino)ethyl 4-chloro-3-nitrobenzoate(2.5 g, 9.1 mmol) and 2d (2.0 g, 9.1 mmol) in anhydrous NMP (5 ml) wasadded triethylamine (1.3 ml, 9.1 mmol), and the mixture was stirred at80° C. for 4 hours. The cooled mixture was poured into ice-water (100ml) and extracted with ethyl acetate (4×20 ml). The combined organicextracts were dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column-chromatography on silicagel using a mixture of dichloromethane and methanol (9:1 v/v) as theeluent to yield 2-(dimethylamino)ethyl3-nitro-4-(3-(1-acetylpiperazin-4-yl)anilino)benzoate (1 g, 24%). Thisintermediate product was dissolved in ethanol (50 ml) and washydrogenated quantitatively at ambient pressure, using Pd (5% onactivated carbon) as the catalyst. The resulting diamine was dissolvedin THF (50 ml) and triethyl orthoformate (0.7 ml, 4.2 mmol) was added,together with a catalytic amount of pTSA. The mixture was heated toreflux for 1 hour. The solvent was removed under reduced pressure andthe residue was partitioned between aqueous sodium carbonate (1M) andethyl acetate. The organic phase was dried over sodium sulfate andconcentrated under reduced pressure, and the residue waschromatographied on silica gel using a mixture of dichloromethane,methanol and aqueous ammonia (90:10:1) as the eluent. The productisolated from the eluate was treated with activated carbon in refluxingethanol and the is product thus obtained was triturated with petroleumether to yield 4i (0.18 g, 20%). M.p. 101-103° C.

The following compound was prepared analogously:

5-((2-(Dimethylamino)ethyl)oxycarbonyl)-l-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole (4j).¹H-NMR (CDCl₃, 500 MHz): 1.29 ppm (t, 3H), 2.44 ppm (s, 6H), 2.77 ppm(t, 4H), 2.88 ppm (t, 2H), 3.28 (s, 2H), 3.33 ppm (t, 4H), 4.21 ppm (q,2H), 4.54 ppm (t, 2H), 6.94 ppm (d, 1H), 6.96ppm (s, 1H), 7.02 ppm (d,1H), 7.44 ppm (t, 1H), 7.55 ppm (d, 1H), 8.06 ppm (d, 1H), 8.17 ppm (s,1H), 8.58 ppm (s, 1H).

Example 22

5-((N,N-Diethylcarboxamido)methyloxycarbonyl)-1-(3-(4-ethoxycarbonylmethyl)-piperazin-1-yl)phenyl)benzimidazole(4k₁) and5-((N,N-diethylcarboxamido)-methyloxycarbonyl)-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole(4k₂): These compounds were prepared from (N,N-diethylcarboxamido)methyl4-chloro-3-nitrobenzoate (1h) and 2e and 2d, respectively as describedin Example 21.

1h was prepared as follows: To a solution of 4-chloro-3-nitrobenzoicacid (5.0 g, 24.8 mmol) in anhydrous DMF (25 ml) was added sodium iodide(0.37 g, 2.5 mmol), triethylamine (6.9 ml, 49.6 mmol) and2-chloro—N,N-diethylacetamide (3.4 ml, 24.8 mmol). The resulting mixturewas stirred at room temperature overnight. The mixture was poured intoice-water (100 ml) and the oily precipitate was filtered off andredissolved in ethyl acetate. This solution was dried over sodiumsulfate and evaporated to dryness to yield 1 h (7.46 g, 96%) as a yellowoil.

Example 23

4-Fluoro-3-nitrophenylacetic acid (1i): A suspension of4-fluorophenylacetic acid (10.0 g, 64.9 mmol) in concentrated sulfuricacid (100 ml) was cooled to 0° C. Concentrated nitric acid (4.5 ml, 65mmol) was added drop-wise, keeping the temperature at 0-5° C. At the endof the addition the mixture was poured into ice-water (400 ml). Theprecipitate was filtered off, washed thoroughly with water and driedwith suction to yield 1i (9.11 g,70%).

Example 24

5-(Methoxycarbonylmethyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole,hydrochloride (4l₁): To a suspension of 1i (3.0 g, 15.1 mmol) inanhydrous NMP (2 ml) was added 2c (2.88 g, 15.1 mmol) and triethylamine(2.1 ml, 30.2 mmol). The mixture was stirred at 80° C. under a stream ofnitrogen overnight. The cooled mixture was poured into a mixture ofdiethyl ether and petroleum ether (100 ml, 1:1 v/v) resulting inseparation of an oily lower phase. The mixture was decanted and the oilwas dissolved in dichloromethane and eluted through silica gel with amixture of dichloromethane and methanol (4:1 v/v) to yield3-nitro-4-(3-(4-methylpiperazin-1-yl)phenylamino)-phenylacetic acid(1.63 g, 29%). This acid (0.64 g, 1.73 mmol) was dissolved in methanoland concentrated hydrochloric acid (0.2 ml) was added. The mixture washeated to reflux for 4 days. The solvent was removed under reducedpressure and the residue was purified by column-chromatography on silicagel using a mixture of dichloromethane, methanol and aqueous ammonia(90:10:1 v/v/v) as the eluent to leave the ester (0.47 g, 71%) as a redoil. This oil was hydrogenated in methanol at ambient pressure using Pd(5% on activated carbon) as the catalyst to yield the correspondingdiamine (0.38 g). This diamine was treated with triethyl orthoformate(0.35 ml, 2.14 mmol) and a catalytic amount of pTSA in THF (5 ml) at 80°C. for 30 min. The solvent was evaporated and the residue waspartitioned between aqueous sodium hydroxide (1M) and ethyl acetate. Theorganic phase was dried over sodium sulfate, concentrated and elutedthrough a silica gel column with a mixture of dichloromethane, methanoland aqueous ammonia (90:10:1 v/v/v). The product precipitated as thehydrochloride by addition of a solution of anhydrous hydrogen chloridein diethyl ether to the eluate. Yield of 4l₁: 0.2 g (41%). M.p. 140-142°C.

The following compounds were prepared analogously:

5-(Ethoxycarbonylmethyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole,hydrochloride (4l₂). M.p. 180-182° C.;

5-(Methoxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole,hydrochloride (4l₃). M.p. 164-165° C. Prepared from 1i and 2o; and

5-(Ethoxycarbonyl)-1-(3-(4-morfolinyl)phenyl)benzimidazole,hydrochloride (4l₄). M.p. 168-169° C. Prepared from 1i and 2o.

Example 25

5-((1-Methylpyrrolidin-2-yl)methoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole(4m) was prepared in analogy with Example 21 from(1-methylpyrrolidin-2-yl)methyl 4-chloro-3-nitrobenzoate and 2e. ¹H-NMR(CDCl₃, 500 MHz): 1.10 ppm (t, 3H), 1.66 ppm (broad, 2H), 1.78 ppm(broad, 1H), 1.94 ppm (broad, 1H), 2.29 ppm (broad, 1H), 2.43 ppm (s,3H), 2.60 ppm (t, 4H), 2.70 ppm (broad, 1H), 3.10 ppm (superimposed s,2H and broad, 1H), 3.15 ppm (t, 4H), 4.02 ppm (q, 2H), 4.28 ppm (broad,2H), 6.75 ppm (d, 1H), 6.78 ppm (s, 1H), 6.83 ppm (d, 1H), 7.24 ppm (t,1H), 7.36 ppm (d, 1H), 7.87 ppm (d, 1H), 7.98 ppm (s, 1H), 8.38 ppm (s,1H).

Example 26

5-Acetyl-1-(3-(1-methyl-4-piperidyloxycarbonyl)phenyl)benzimidazoleO-isopropyl oxime (5a₁): A mixture 1b (11.0 g, 60.2 mmol), ethyl3-aminobenzoate (9.9 g, 6.2 mmol) and triethylamine (8.34 ml, 60.2 mmol)in anhydrous NMP (5 ml) was heated to 130° C. with stirring under astream of nitrogen for 4 hours. The cooled mixture was poured intoice-water (100 ml). Ethanol (10 ml) was added and the mixture wasstirred until crystallization was completed. The precipitate wasfiltered off, washed with water and dried to yield ethyl(4-acetyl-2-nitrophenyl)aminobenzoate (19.1 g, 97%). This ester washydrogenated quantitatively in a mixture of ethanol (400 ml) anddichloromethane (100 ml) using Pd (5% on activated carbon) as thecatalyst. The resulting diamine was heated to reflux in formic acid (100ml) for 1 hour. The cooled mixture was poured into ice-water (400 ml)and the precipitate was filtered off, washed with water and dried toyield 5-acetyl-1-(3-ethoxycarbonyl)phenylbenzimidazole (16.4 9, 91%).

The above ester (10 g, 32.5 mmol) was dissolved in dimethoxyethane (200ml) and aqueous sodium hydroxide (100 ml, 1M) was added. The mixture washeated to 80° C. for 1 hour and the organic solvent was removed underreduced pressure. The residue was diluted with ice-water (100 ml) andmixture was neutralized by addition of glacial acetic acid. Theprecipitate was filtered off, washed with water and dried to yield5-acetyl-1-(3-carboxyphenyl)benzimidazole (7.56 g, 83%).

This acid (4.66 g, 16.64 mmol) was suspended in anhydrous, peroxide freeTHF (50 ml) and heated to reflux. Carbonyldiimidazole (5.4 g, 33.28mmol) was added in portions over 3 hours. Reflux was continuedovernight. The solvent was removed under reduced pressure and theresidue was triturated with diethyl ether to leave the crude5-acetyl-1-(3-carboxyimidazolide)phenylbenzimidazole (6.9 g),contaminated with imidazole and carbonyldiimidazole.

To a solution of 1-methyl-4-hydroxypiperidine (1.06 ml, 9.1 mmol) in amixture of anhydrous THF (5 ml) and anhydrous DMF (5 ml) was addedsodium hydride (0.36 g 60% dispersion in mineral oil, 9.1 mmol) atambient temperature. When the evolution of hydrogen had ceased, theabove crude imidazolide (1.5 g),was added and the mixture was heated to40° C. overnight. The cooled mixture was filtered and the filter-cakewas washed with THF. The combined filtrate and washings was diluted withwater and extracted with ethyl acetate. The organic extract was driedover sodium sulfate and concentrated by evaporation of solvent, and theresidue was purified by column-chromatography using a mixture ofdichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v) as theeluent. This procedure yielded5-acetyl-1-(3-(1-methyl-4-piperidyloxycarbonyl)phenyl)benzimidazole(0.56 g, 33%), which was treated with O-i-propylhydroxylamine,hydrochloride (0.17 B, 1.52 mmol) in refluxing ethanol (5 ml) overnight.Evaporation of solvent left a crude product, which uponcolumn-chromatography in silica gel using a mixture of dichloromethane,methanol and aqueous ammonia (90:10:1 v/v/v) as the eluent yielded pure5a₁ (80 mg). M.p. 106-1070° C.

The following compounds were prepared analogously:

5-Acetyl-1-(3-(1-methyl-3-piperidyloxycarbonyl)phenyl)benzimidazoleO-i-propyl oxime (5a₂). M.p. 83-84° C.; and

5-Acetyl-1-(3-(2-picolyloxycarbonyl)phenyl)benzimidazole O-i-propyloxime 5a₃). M.p. 104-106° C.

Example 27

5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole was preparedas described in Example 12. From this ketone the following O-alkylatedoximes were prepared by treatment with the appropriate O-alkylatedhydroxylamines under standard conditions:

5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazoleO-ethoxycarbonyl-methyl) oxime, hydrochloride (5b₁). M.p. 73-75° C.;

5-Acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazoleO-(methoxycarbonylmethyl) oxime (5b₂). M.p. 104-106° C.; and

5-Acetyl-I -(3-(1-methylpiperidin-3-yl)phenyl)benzimidazoleO-(methoxycarbonyl-(dimethyl)methyl) oxime (5b₃). M.p. 113-115° C.

Example 28

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazole wasprepared as described in Example 12. From this ketone the followingO-alkylated oximes were prepared by treatment with the appropriateO-alkylated hydroxylamines under standard conditions:

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazoleO-(methoxy-carbonylmethyl) oxime (5c₁). M.p. 117-119° C.;

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazolO-(ethoxy-carbonylmethyl) oxime, hydrochloride (5c₂). ¹H-NMR (CDCl₃, 500MHz): 1.23 ppm (t, 3H), 2.36 ppm (s, 3H), 2.66 ppm (t, 2H), 2.74 ppm(broad, 4H), 3.30 ppm (t, 4H), 3.67 ppm (t, 2H), 4.17 ppm (q, 2H), 4.70ppm (s, 2H), 6.92 ppm (“m”, 3H), 7.37 ppm (t, 1H), 7.43 (d, 1H), 7.67ppm (d, 1H), 8.01 ppm (s, 1H), 8.05 ppm (s, 1H); and

5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)benzimidazoleO-(ethoxy-carbonyl(dimethyl)methyl) oxime, hydrochloride (5c₃). ¹H-NMR(DMSO-d₆, 500 MHz): 1.16 ppm (t, 3H), 1.52 ppm (s, 6H), 2.32 ppm (s,3H), 3.11 (“m”, 4H), 3.33 ppm (t, 2H), 3.60 ppm (d, 2H), 3.81 ppm (“s”,2H), 3.96 ppm (d, 2H), 4.12 ppm (q, 2H), 7.22 ppm (d, 1H), 7.25 ppm (d,1H), 7.40 ppm (s, 1H), 7.78 ppm (d, 1H), 7.86 ppm (d, 1H), 8.08 ppm (s,1H), 9.73 ppm (s, 1H), 11.00 ppm (broad, 1H).

Example 29

5-Acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazoleoxime (5d₁) was prepared from 1b and 2e under the conditions describedin Example 12. M.p. 154-156° C.; and

5-Acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperidin-1-yl)phenyl)benzimidazoleO-ethyl oxime (5d₂). M.p. 119-120° C. was prepared analogously.

Example 30

5-Acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole and5-acetyl-t-(3-(4-morfolinyl)phenyl)benzimidazole were prepared asdescribed in Example 12. From these ketones the following O-alkylatedoximes were prepared by treatment with the appropriate O-alkylhydroxylamines under standard conditions:

5-Acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazoleO-(methoxycarbonyl-(dimethyl)methyl) oxime (5e₁). M.p. 119-120° C.;

5-Acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazoleO-(methoxycarbonyl-methyl) oxime (5e₂). M.p. 137-139° C.; and

5-Acetyl-1-(3-(4-morfolinyl)phenyl)benzimidazoleO-(methoxycarbonylmethyl) oxime (5e₃). M.p. 149-150° C.

Example 31

5-Acetyl-1-(3-(4-(methoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazoleO-i-propyl oxime (5f₁). To a solution of5-acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole (see Example12) (8.3 g, 23.0 mmol) in dimethoxyethane (140 ml) was added aqueoussodium hydroxide (70 ml, 1M) and the mixture was heated to 80° C.overnight. The organic solvent was removed under reduced pressure andthe residue was diluted with water and extracted with dichloromethane.The organic phase was concentrated and purified by column-chromatographyon silica gel using a mixture of dichloromethane, methanol and aqueousammonia (90:10:1 v/v/v) as the eluent. The concentrated eluate wastriturated with diethyl ether to yield5-acetyl-1-(3-(piperazin-1-yl)phenyl)benzimidazole (4.81 g, 65%) as redcrystals. This product (2.0 g, 6.25 mmol) was dissolved in refluxingethanol (20 ml). O-Isopropylhydroxylamine, hydrochloride (0.7 g, 6.25mmol) was added and reflux was continued for 5 hours. The reactionmixture was evaporated to dryness and the residue was partitionedbetween aqueous sodium hydroxide (1M) and dichloromethane. The organicphase was dried and concentrated and eluted through silica gel with amixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v)to yield 5-acetyl-1-(3-(1-piperazinyl)phenyl)-benzimidazole O-i-propyloxime (1.75 g, 74%). This product was alkylated with methyl bromoacetatein anhydrous DMF on the presence of triethylamine at room temperature toyield 5f₁ (0.48 g, 77%). M.p. 120-121° C.

Alkylation with diethyl ethoxymethylenemalonate afforded5-acetyl-1-(3-(4-(2,2-bis(ethoxycarbonyl)ethenyl)piperazin-1-yl)phenyl)benzimidazoleO-i-propyl oxime (5f₂). M.p. 128-129° C.

Example 32

5-Formyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole and5-formyl-1-(3-(4-morfolinyl)phenyl)benzimidazole were prepared asdescribed in Example 11. These aldehydes were condensed withO-(methoxycarbonyl(dimethyl)methyl)hydroxylamine under standardconditions to yield:

5-Formyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazoleO-(methoxycarbonyl-(dimethyl)methyl) oxime, hydrochloride (5 g₁). M.p.199-201° C.; and

5-Formyl-1-(3-(4-morfolinyl)phenyl)benzimidazoleO-(methoxycarbonyl)dimethyl)-methyl) oxime, hydrochloride (5 g₂). M.p.175-177° C.

Example 33

5-(5-Isoxazolyl)-1-(3-(methoxycarbonyl)phenyl)benzimidazole (6a₁): To asuspension of 5-acetyl-1-(3-(methoxycarbonyl)phenyl)benzimidazole(prepared in analogy with Example 26) (0.6 g, 2.04 mmol) in anhydrousDMF (5 ml) was added dimethylformaldehyde dimethylacetal (0.43 ml, 3.24mmol) and the mixture was heated to 120° C. under a stream of nitrogenovernight. The cooled mixture was poured into ice-water (25 ml) and theprecipitate was filtered off and purified by column-chromatography onsilica gel using a mixture of ethyl acetate and methanol (9:1 v/v) asthe eluent to yield5-(3-dimethylaminoprotenoyl)-1-(3-(ethoxycarbonyl)phenyl)benzimidazole(0.44 g, 62%).

The above intermediate (0.42 g, 1.2 mmol) was suspended in methanol (10ml) and hydroxylamine, hydrochloride (0.21 g, 3 mmol) was added. Themixture was heated to reflux for 2 hours. The cooled mixture was pouredinto ice-water and the precipitate was filtered off, washed with waterand dried. This crude product was chromatographied on silica gel usingethyl acetate as the eluent to yield 6a₁ (0.2 g, 52%). M.p. 190-191° C.

The following compound was prepared analogously:

5-(5-Isoxazolyl)-1-(3-ethoxycarbonyl)phenyl benzimidazole (6a₂). M.p.156-157° C.

Example 34

1-(3-Ethoxycarbonyl)phenyl-5-phenylbenzimidazole (6b₁): To a suspensionof 1e (8.0 g, 36.9 mmol) and ethyl 3-aminobenzoate (6.1 g, 36.9 mmol) inanhydrous NMP (5 ml) was added trethylamine (5.1 ml, 36.9 mmol) and themixture was stirred in a nitrogen atmosphere at 140° C. overnight. Thecooled reaction mixture was diluted with water (50 ml) and extractedwith ethyl acetate (3×20 ml). The organic extracts were dried oversodium sulfate and concentrated under reduced pressure. The productprecipitated from the residue upon trituration with a mixture of diethylether and petroleum ether (1:1). Yield of ethylN-(3-nitrobiphenyl-4-yl)aminobenzoate: 7.46 g (56%).

This ester was quantitatively hydrogenated in ethanol at ambientpressure using Pd (5% on activated carbon) as the catalyst. Theresulting diamine was treated with formic acid (50 ml) at 80° C. for 1hour. The cooled reaction mixture was poured into ice-water (200 ml) andwas rendered alkaline by addition of aqueous sodium hydroxide (10M). Themixture was extracted with ethyl acetate and the extract was dried oversodium sulfate and evaporated to dryness. The residue was trituratedwith a mixture of petroleum ether and diethyl ether (9:1) to leave 6b₁(5.8 g, 85%). M.p. 122-123° C.

The following compound was prepared analogously from 1e and 2e:

5-phenyl-1-(3-(4-ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole(6b₂). M.p. 121-122° C.

Example 35

5-phenyl-1-(3-(2-picolyloxycarbonyl)phenyl)benzimidazole (6b₃): To asolution of 6b, (5.30 g, 15.5 mmol) in dimethoxyethane (100 ml) wasadded aqueous sodiumhydroxide (50 ml, 1 M) and the mixture was heated to40° C. for 2 hours. The organic solvent was removed by evaporation andthe residue was diluted with an equal volume of water and acidified byaddition of glacial acetic acid. The precipitate was filtered off,washed with water and dried to yield 5-phenyl-1-(3-carboxyphenyl)benzimidazole (4.26 g, 88%). M.p. 289-291° C.

This acid was treated with thionyl chloride (25 ml) at 80° C. for 2hours. Excess thionyl chloride was removed by evaporation and theresidue was triturated with diethyl ether to leave the correspondingcarboxylic acid chloride, quantitatively.

To a suspension of the above carboxylic acid chloride (1.0 g, 3 mmol) inanhydrous THF (10 ml) was added 2-pyridylcarbinol (0.29 ml, 3 mmol) andthe mixture was stirred in a nitrogen atmosphere at 40° C. overnight.The solvent was removed under reduced pressure, and the residue wasstirred in aqueous sodium bicarbonate (1M). The precipitate was filteredoff, washed with water and dried. Column-chromatography on silica gelusing a mixture of ethyl acetate and methanol (9:1 v/v) as the eluentafforded 6b₃ (0.29 g, 24%). M.p. 149-150° C.

The following compounds were prepared analogously:

5-phenyl-1-(3-(3-picolyloxycarbonyl)phenyl)benzimidazole, hydrochloride(6b₄). M.p. 195-197° C.;

5-phenyl-1-(3-(1-methylpiperid-3-yloxycarbonyl)phenyl)benzimidazole,hydrochloride (6b₅). M.p. 180-191° C.; and

5-phenyl-1-(3-((1-methylpiperid-4-yl)oxycarbonyl)phenyl)benzimidazole,hydrochloride (6b₆). M.p. 187-188° C.

Example 36

5-(3-furanyl)-1-(3-(ethoxycarbonyl)phenyl)benzimidazole(6c₁) To asolution of 1d (2.07 g, 10 mmol) in NMP (2 ml) was added ethyl3-aminobenzoate (1.82 g, 11 mmol) and triethylamine and the mixture washeated to 110° C. in a nitrogen atmosphere overnight. The mixture wasdiluted with ice-water and extracted with ethyl acetate. Theconcentrated extract was purified by column-chromatography on silica gelusing a mixture of petroleum ether and ethyl acetate (9:1 v/v) to yieldethyl 3-(N-(4-(3-furanyl)-2-nitrophenyl))aminobenzoate (1.18 g, 34%).This ester was hydrogenated in ethanol at ambient pressure using Pd (5%on activated carbon) as the catalyst. The resulting diamine (1.07 g) wastreated with triethyl orthoformate (1.11 ml, 6.64 mmol) and a catalyticamount of pTSA in refluxing THF (10 ml). Column-chromatographic work-upof the concentrated reaction mixture using ethyl acetate as the eluentafforded 6c₁ (0.66 9, 56%).

M.p. 87-89° C.

From some preparations the following by-product was isolated:

5-(3-Tetrahydrofuranyl)-1-(3-(ethoxycarbonyl)phenyl)benzimidazole,hydrochloride (6c₂). M.p. 168-171° C.

The following compounds were prepared analogously from 1d and 2e, 2g,2l, 2m, 2n and 2-(dimethylamino)ethyl 3-aminobenzoate, respectively:

5-(3-Furanyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole(6c₃). M.p. 110-1120° C.;

5-(3-Furanyl)-1-(3-(4-(t-butoxycarbonyl)piperazin-1-yl)phenyl)benzimidazole(6c₄). M.p. 162-164° C.;

5-(3-Furanyl)-1-(3-(4-(methoxycarbonylmethyl)piperazin-1-yl)phenyl)benzimidazole(6c₅). M.p. 124-125° C.;

5-(3-Furanyl)-l-(31(4-(2,2-bis(ethoxycarbonyl)ethenyl)piperazin-1-yl)phenyl)benzimidazole(6c₆). M.p. 97-1 02° C.;

5-(3-Furanyl)-1-(3-(4-(2-(methoxycarbonyl)ethenyl)piperazin-1-yl)phenyl)benzimidazole(6c₇). M.p. 131-133° C.; and

5-(3-Furanyl)-1-(3-(2-(dimethylamino)ethyloxycarbonyl)phenyl)benzimidazole,hydrochloride (6c₈). M.p. 168-171° C.

Example 37 Biological Activity

Tissue Preparation: Preparations are performed at 0-4° C. unlessotherwise indicated.

Cerebral cortex from male Wistar rats (150-200 g) is homogenized for5-10 sec in 20 ml Tris-HCl (30 mM, pH 7.4) using an Ultra-Turraxhomogenizer. The suspension is centrifuged at 27,000×g for 15 min, andthe pellet is washed three times with buffer (centrifuged at 27,000×gfor 10 min). The washed pellet is homogenized in 20 ml of buffer andincubated on a water bath (37° C.) for 30 min to remove endogenous GABAand then centrifuged for 10 min at 27,000×g. The pellet is thenhomogenized in buffer and centrifuged for 10 min at 27,000×g. The finalpellet is resuspended in 30 ml buffer and the preparation is frozen andstored at −20° C.

Assay: The membrane preparation is thawed and centrifuged at 2° C. for10 min at 27,000×g. The pellet is washed twice with 20 ml 50 mMTris-citrate, pH 7.1 using an Ultra-Turrax homogenizer and centrifugedfor 10 min at 27,000×g. The final pellet is resuspended in 50 mMTris-citrate, pH 7.1 (500 ml buffer per g of original tissue), and thenused for binding assays. Aliquots of 0.5 ml tissue are added to 25 μl oftest solution and 25 μl of ³H-FNM (1 nM, final concentration), mixed andincubated for 40 min at 2° C. Non-specific binding is determined usingclonazepam (1 μM, final concentration). After incubation the samples areadded 5 ml of ice-cold buffer and poured directly onto Whatman GF/Cglass fibre filters under suction and immediately washed with 5 mlice-cold buffer. The amount of radioactivity on the filters isdetermined by conventional liquid scintillation counting. Specificbinding is total binding minus non-specific binding.

The test value is calculated as the IC₅₀ (the concentration (nM) of thetest substance which inhibits the specific binding of ³H-FNM by 50%).

Test results obtained by testing selected compounds of the presentinvention appear from table 7, below.

TABLE 7 Biological Activity Test compound IC₅₀ (μM)5-Acetyl-1-[3-(1-methylpiperidin-3-yl)- 0.018 phenyl]benzimidazoleO-ethyl oxime 5-Cyano-1-(3-(1 pyrrolidinyl)phenyl)benzimidazole 0.0415-Formyl-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole 0.004 oxime5-(3-Furanyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl) 0.005phenyl)benzimidazole 5-(Ethoxycarbonyl)-1-(3-(4-(methoxycarbonylmethyl)0.050 piperazin-1-yl)phenyl)-benzimidazole, hydrochloride5-(3-Picolyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl) 0.080phenyl)benzimidazole5-(Methoxycarbonylmethyl)-1-(3-(4-methylpiperazin-1-yl) 0.025phenyl)benzimidazole, hydrochloride5-Acetyl-1-(3-(2-picolyloxycarbonyl)phenyl) 0.002 benzimidazoleO-i-propyl oxime 5-Acetyl-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)0.019 benzimidazole O-(methoxy-carbonylmethyl) oxime5-Acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperidin-1-yl)- 0.027 phenyl)benzimidazole O-ethyl oxime 5-(5-Isoxazolyl)-1-(3-ethoxycarbonyl)phenylbenzimidazole 0.0035-Phenyl-1-(3-(2-picolyloxycarbonyl)phenyl)benzimidazole 0.0085-(3-Furanyl)-1-(3-(4-(2,2-bis(ethoxycarbonyl)ethenyl) 0.007piperazin-1-yl)phenyl)-benzimidazole

Penylenetetrazol (PTZ, Sigma) induces clonic convulsions in mice afteri.v. infusion. Antagonism of penylenetetrazol-induced convulsions isconsidered predictive for drugs effective against various forms ofepilepsia. The compounds of the present invention inhibits PTZ inducedconvulsions in mice at low doses.

Example 38 Biological Activity

In Vivo Inhibition of ³H-flunitrazepam ([3H]FNM) Binding

[³H]FNM can be used for In vivo receptor labelling studies in mouse.Accumulation of [³H]FNM binding will occur all over the brain asGABA_(A) receptors are widely distributed. The specific binding of[³H]FNM can be partly or completely prevented by simultaneous or prioradministration of pharmacologically active benzodiazepines or by somebenzodiazepine-like compounds.

Method: All test substances used are solutions prepared in 10% Tween 80.Groups of three female NMRI mice (25 g) are injected i.v. via the tailvein with 5.0 mCi of [3H]FNM in 0.2 ml saline. 15 min. after injectionwith [³H]FNM the test substance is administered i.v. Twenty min afterinjection with [³H]FNM, mice are killed by decapitation, the forebrainsrapidly excised and homogenized in 12 ml of ice-cold 50 mM Tris-citrate,pH 7,1 using an Ultra-Turrax homogenizer. Three aliquots of 1 ml areimmediately filtered through GF/C glass fiber filters and washed with2×5 ml of ice-cold buffer.

The amounts of radioactivity on the filters and in 200 mL of thehomogenate are determined by conventional scintillation counting. Groupsof untreated mice serves as controls.

To determine non-specific binding groups of mice are injected withclonazepam (25 mg/kg) i.p. 10 min before [³H]FNM injection. Specificbinding is the amount of binding in controls minus the amount of bindingin clonazepam treated mice.

Results: The ED₅₀value is determined from dose response curves. Theresults show that the compounds of the present invention have a veryfavorable kinetic behavior.

What is claimed is:
 1. A chemical compound represented by the formula(I)

in which formula (I), o is 0, 1, 2 or 3; R¹ represents an alkyl groupwhich is unsubstituted or substituted one or more times withsubstituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,halogen, trifluoromethyl, cyano, amino, and nitro; R¹¹ represents a, anamino C₁₋₄-alkyl-oxycarbonyl group, anN—C₁₋₄-alkyl-amino-C₁₋₄-alkyl-oxycarbonyl group, anN,N-di-(C₁₋₄-alkyl)-amino-C₁₋₄-alkyl-oxycarbonyl group; or a piperidinylgroup, a piperidinyl-oxycarbonyl group, a pyrrolidinyl group, apyrrolidinyl-C₁₋₃-alkyl group, a piperazinyl group, a homopiperazinylgroup, a tetrahydropyridyl group, a picolyl-oxycarbonyl group, whichgroups are unsubstituted or substituted one or more times withsubstituents selected from C₁₋₄-alkyl, C₁₋₄-alkyl-oxy,C₁₋₄-alkyl-oxycarbonyl, C₁₋₄-alkyl-oxycarbonyl-C₁₋₄-alkyl,C₁₋₄-alkenyl-oxycarbonyl-C₁₋₄-alkyl,C₁₋₄-alkenyl-(oxycarbonyl-C₁₋₄-alkyl acetyl, hydroxy-C₁₋₄-alkyl,carboxamido, N—C₁₋₄-alkyl-carboxamido-C₁₋₄-alkyl, andN,N-di-C₁₋₄-alkyl-carboxamido-C₁₋₄-alkyl; or a pharmaceuticallyacceptable salt thereof, or an N-oxide thereof.
 2. The chemical compoundaccording to claim 1, wherein o is zero and R¹ is tert-butyl.
 3. Thechemical compound according to claim 1, wherein R¹¹ is selected from1-piperidinyl, 1-pyrrolidinyl, 4-methyl-1-piperazinyl,1-methyl-3-piperidinyl, (1-methyl-4-piperidinyl)oxycarbonyl,(1-methyl-3-piperidinyl)oxycarbonyl, 2-picolyl-oxycarbonyl,3-picolyl-oxycarbonyl, 1-acetyl-4-piperazinyl,4-(2-hydroxyethyl)piperazin-1-yl, (1-pyrrolidinyl)methyl,4-methylhomopiperazin-1-yl, 1-methyl-1,2,3,6-tetrahydropyrid-5-yl,4-(N,N-diethyl-carboxamidomethyl)-piperazin-1-yl,4-(N,N-dimethyl-carboxamidomethyl)-piperazin-1-yl,4-(methoxycarbonylmethyl)-1-piperazinyl,4-(ethoxycarbonylmethyl)-1-piperazinyl,4-(t-butoxycarbonylmethyl-1-piperazinyl,4-(diethylcarboxamido-methyl)piperazin-1-yl,4-(2,2-bis(ethoxycarbonyl)-ethenyl)piperazin-1-yl,4-(2-methoxycarbonyl-ethenyl)piperazin-1-yl, methoxycarbonyl,ethoxycarbonyl, 2-amino-ethoxycarbonyl, 2-(N-methylamino)ethoxycarbonyl,and 2-(N,N-dimethylamino) ethoxycarbonyl.
 4. The chemical compoundaccording to claim 2, wherein R¹¹ is selected from 1-piperidinyl,1-pyrrolidinyl, 4-methyl-1-piperazinyl, 1-methyl-3-piperidinyl,(1-methyl-4-piperidinyl)oxycarbonyl,(1-methyl-3-piperidinyl)oxycarbonyl, 2-picolyl-oxycarbonyl,3-picolyl-oxycarbonyl, 1-acetyl-4-piperazinyl,4-(2-hydroxyethyl)piperazin-1-yl, (1-pyrrolidinyl)methyl,4-methylhomopiperazin-1-yl, 1-methyl-1,2,3,6-tetrahydropyrid-5-yl,4-(N,N-diethyl-carboxamidomethyl)-piperazin-1-yl,4-(N,N-dimethyl-carboxamidomethyl)-piperazin-1-yl,4-(methoxycarbonylmethyl)-1-piperazinyl, 4-(ethoxycarbonylmethyl)-l-piperazinyl, 4-(t-butoxycarbonylmethyl-1-piperazinyl,4-(diethylcarboxamido-methyl)piperazin-1-yl,4-(2,2-bis(ethoxycarbonyl)-ethenyl)piperazin-1-yl,4-(2-methoxycarbonyl-ethenyl)piperazin-1-yl, methoxycarbonyl,ethoxycarbonyl, 2-amino-ethoxycarbonyl, 2-(N-methylamino)ethoxycarbonyl,and 2-(N,N-dimethylamino) ethoxycarbonyl.
 5. The chemical compoundaccording to claim 1, which is5-t-butyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole; or apharmaceutically acceptable salt thereof, or an N-oxide thereof.
 6. Apharmaceutical composition comprising an effective amount of a chemicalcompound according to any one of claims 1, 2, or 3 through 5, or apharmaceutically acceptable salt thereof or an N-oxide thereof, and apharmaceutically acceptable excipient, carrier. or diluent.
 7. A methodof treating a disease of a living animal body, which disease isresponsive to enhancing effect on the action of GABA_(A) which methodcomprises administration of a therapeutically effective amount of achemical compound according to any one of claims 1, 2, or 3, through 5.8. The method according to claim 7, wherein the living animal body ishuman and the disease is selected from anxiety, anesthesia, andepilepsy.